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Khamoui 2020 Physiol Genomics + (Cachexia is a life-threatening complicatio … Cachexia is a life-threatening complication of cancer traditionally characterized by weight loss and muscle dysfunction. Cachexia, however, is a systemic disease that also involves remodeling of non-muscle organs. The liver exerts major control over systemic metabolism yet its role in cancer cachexia is not well-understood. To advance the understanding of how the liver contributes to cancer cachexia, we used quantitative proteomics and bioinformatics to identify hepatic pathways and cellular processes dysregulated in mice with moderate and severe colon-26 tumor-induced cachexia. ~300 differentially expressed proteins identified during the induction of moderate cachexia were also differentially regulated in the transition to severe cachexia. KEGG pathways enrichment revealed representation by oxidative phosphorylation, indicating altered hepatic mitochondrial function as a common feature across cachexia severity. Glycogen catabolism was also observed in cachexic livers along with decreased pyruvate dehydrogenase protein X component (Pdhx), increased lactate dehydrogenase A chain (Ldha), and increased lactate transporter Mct1. Together this suggests altered lactate metabolism and transport in cachexic livers, which may contribute to energetically inefficient inter-organ lactate cycling. Acyl-CoA synthetase-1 (ACSL1), known for activating long-chain fatty acids, was decreased in moderate and severe cachexia based on LC-MS/MS and immunoblotting. ACSL1 showed strong linear relationships with percent body weight change and muscle fiber size (R2=0.73-0.76, P<0.01). Mitochondrial coupling efficiency, which is compromised in cachexic livers to potentially increase energy expenditure and weight loss, also showed a linear relationship with ACSL1. These findings suggest altered mitochondrial and substrate metabolism of the liver in cancer cachexia, and possible hepatic targets for intervention.nd possible hepatic targets for intervention.)
Branca 2020 Front Cell Dev Biol + (Cadmium (Cd) is a well-known heavy metal a … Cadmium (Cd) is a well-known heavy metal and environmental toxicant and pollutant worldwide, being largely present in every kind of item such as plastic (toys), battery, paints, ceramics, contaminated water, air, soil, food, fertilizers, and cigarette smoke. Nowadays, it represents an important research area for the scientific community mainly for its effects on public health. Due to a half-life ranging between 15 and 30 years, Cd owns the ability to accumulate in organs and tissues, exerting deleterious effects. Thus, even at low doses, a Cd prolonged exposure may cause a multiorgan toxicity. Mitochondria are key intracellular targets for Cd-induced cytotoxicity, but the underlying mechanisms are not fully elucidated. The present review is aimed to clarify the effects of Cd on mitochondria and, particularly, on the mitochondrial electron transport chain.he mitochondrial electron transport chain.)
Zhang 2020 Chemosphere + (Cadmium (Cd) is a widespread environment c … Cadmium (Cd) is a widespread environment contaminant due to the development of electroplating and metallurgical industry. Cd can be enriched by organisms via food chain, causing the enlarged environmental problems and posing threats to the health of humans. Polydatin (PD), a natural stilbenoid compound derived from ''Polygonum cuspidatum'', shows pronouncedly curative effect on oxidative damage. In this work, the protective effects of PD on oxidative damage induced by Cd in ''Musca domestica'' (housefly) larvae were evaluated. The larvae were exposed to Cd and/or PD, subsequently, the oxidative stress status, mitochondria activity, oxidative phosphorylation efficiency, and survival rate were assessed. Cd exposure generated significant increases of malondialdehyde (MDA), reactive oxygen species (ROS) and 8-hydroxy-2-deoxyguanosine (8-oxoG) in the housefly larvae, causing mitochondrial dysfunction and survival rate decline. Interestingly, pretreatment with PD exhibited obviously mitochondrial protective effects in the Cd-exposed larvae, as evidenced by reduced MDA, ROS and 8-oxoG levels, and increased activities of superoxide dismutase (SOD), mitochondrial electron transfer chain, and mitochondrial membrane potential, as well as respiratory control ratio. These results suggested that PD could attenuate Cd-induced damage via maintaining redox balance, stimulating SOD activity, and regulating mitochondria activity in housefly larvae. As a natural polyphenolic chemical, PD can act as a potential candidate compounds to relieve Cd injury.Copyright © 2020 Elsevier Ltd. All rights reserved. 2020 Elsevier Ltd. All rights reserved.)
Wright 2013 Abstract MiP2013 + (Calcium (Ca2+) is an important intracellul … Calcium (Ca2+) is an important intracellular signalling molecule in mammalian tissues, and has been associated with the regulation of diverse processes, including contraction, secretion, autophagy, ion pumping, and the activation of metabolic enzymes. Mitochondria maintain a calcium gradient between the matrix and the cytoplasm, via the actions of specific transporters in the inner mitochondrial membrane. Under conditions of metabolic dysfunction (such as insulin resistance), mitochondrial calcium homeostasis is often altered (for a recent review, see [1]).With the recent identification of the mitochondrial calcium uniporter (MCU) and associated regulatory proteins, as well as the use of targeted aequorin probes, we are now able to investigate the role of mitochondrial Ca2+ in the regulation of whole-cell adipocyte metabolism [2,3]. Preliminary data suggest that the induction of insulin resistance (by treatment with 100 nM insulin for 24 h) in cultured adipocytes alters the expression of key components of the uniporter (+75% MCUa and +42% MCUb compared to control, P<0.05), and increases Ca2+ uptake into the mitochondria (+76%, P<0.05). Similarly, feeding mice a high-fat-high-sugar diet alters the expression of these genes in visceral white adipose tissue (+54% MCUa and +127% MCUb compared to chow-fed control, P<0.05). Additionally, we saw that direct manipulation of mitochondrial calcium by overexpression of MCUb in cultured adipocytes was able to alter a number of metabolic parameters, including mitochondrial membrane potential, NADH dynamics, and the rate of glucose oxidation. The mechanism and significance of these metabolic alterations is currently under investigation.We theorise that mitochondrial calcium plays an important role in the orchestration of metabolic homeostasis in adipocytes. As such, the MCU may represent an interesting node of metabolic regulation - and therefore therapeutic potential - in times of metabolic dysregulation.ic potential - in times of metabolic dysregulation.)
Vilas-Boas 2023 J Biol Chem + (Calcium (Ca2+) is a … Calcium (Ca2+) is a key regulator in diverse intracellular signaling pathways, and has long been implicated in metabolic control and mitochondrial function. Mitochondria can actively take up large amounts of Ca2+, thereby acting as important intracellular Ca2+ buffers and affecting cytosolic Ca2+ transients. Excessive mitochondrial matrix Ca2+ is known to be deleterious due to opening of the mitochondrial permeability transition pore (mPTP) and consequent membrane potential dissipation, leading to mitochondrial swelling, rupture, and cell death. Moderate Ca2+ within the organelle, on the other hand, can directly or indirectly activate mitochondrial matrix enzymes, possibly impacting on ATP production. Here, we aimed to determine in a quantitative manner if extra or intramitochondrial Ca2+ modulate oxidative phosphorylation in mouse liver mitochondria and intact hepatocyte cell lines. To do so, we monitored the effects of more modest versus supra-physiological increases in cytosolic and mitochondrial Ca2+ on oxygen consumption rates. Isolated mitochondria present increased respiratory control ratios (a measure of oxidative phosphorylation efficiency) when incubated with low (2.4 ± 0.6 μM) and medium (22.0 ± 2.4 μM) Ca2+ concentrations in the presence of complex I-linked substrates pyruvate plus malate and α-ketoglutarate, respectively, but not complex II-linked succinate. In intact cells, both low and high cytosolic Ca2+ led to decreased respiratory rates, while ideal rates were present under physiological conditions. High Ca2+ decreased mitochondrial respiration in a substrate-dependent manner, mediated by mPTP. Overall, our results uncover a Goldilocks effect of Ca2+ on liver mitochondria, with specific "just right" concentrations that activate oxidative phosphorylation. Overall, our results uncover a Goldilocks effect of Ca2+ on liver mitochondria, with specific "just right" concentrations that activate oxidative phosphorylation.)
Clapham 2007 Cell + (Calcium ions (Ca(2+)) impact nearly every … Calcium ions (Ca(2+)) impact nearly every aspect of cellular life. This review examines the principles of Ca(2+) signaling, from changes in protein conformations driven by Ca(2+) to the mechanisms that control Ca(2+) levels in the cytoplasm and organelles. Also discussed is the highly localized nature of Ca(2+)-mediated signal transduction and its specific roles in excitability, exocytosis, motility, apoptosis, and transcription.s, motility, apoptosis, and transcription.)
Giorgi 2018 Nat Rev Mol Cell Biol + (Calcium ions (Ca2+) are some of the most v … Calcium ions (Ca2+) are some of the most versatile signalling molecules, and they have many physiological functions, prominently including muscle contraction, neuronal excitability, cell migration and cell growth. By sequestering and releasing Ca2+, mitochondria serve as important regulators of cellular Ca2+. Mitochondrial Ca2+ also has other important functions, such as regulation of mitochondrial metabolism, ATP production and cell death. In recent years, identification of the molecular machinery regulating mitochondrial Ca2+ accumulation and efflux has expanded the number of (patho)physiological conditions that rely on mitochondrial Ca2+ homeostasis. Thus, expanding the understanding of the mechanisms of mitochondrial Ca2+ regulation and function in different cell types is an important task in biomedical research, which offers the possibility of targeting mitochondrial Ca2+ machinery for the treatment of several disorders.ry for the treatment of several disorders.)
Endlicher 2018 Cesk Fysiol + (Calcium ions play an important role in cel … Calcium ions play an important role in cell metabolism regulation. Mitochondrial permeability transition pore (MPTP) has recently attracted considerable attention. Short, reversible opening of this pore protects cells from oxidative damage, but its long lasting, irreversible opening induces the processes leading to cell death. A wide variety of substances was successfully proven to influence MPTP function either positively or negatively, however the molecular structure of this membrane pore remains unclear. This work summarizes up to date knowledge of MPTP function and regulation, efforts to elucidate molecular structure of the pore and finally we provide a review of diseases with MPTP involved in pathogenesis.seases with MPTP involved in pathogenesis.)
Glancy 2013 Biochemistry + (Calcium is believed to regulate mitochondr … Calcium is believed to regulate mitochondrial oxidative phosphorylation, thereby contributing to the maintenance of cellular energy homeostasis. Skeletal muscle, with an energy conversion dynamic range of up to 100-fold, is an extreme case for evaluating the cellular balance of ATP production and consumption. This study examined the role of Ca(2+) in the entire oxidative phosphorylation reaction network in isolated skeletal muscle mitochondria and attempted to extrapolate these results back to the muscle, ''in vivo''. Kinetic analysis was conducted to evaluate the dose-response effect of Ca(2+) on the maximal velocity of oxidative phosphorylation (VmaxO) and the ADP affinity. Force-flow analysis evaluated the interplay between energetic driving forces and flux to determine the conductance, or effective activity, of individual steps within oxidative phosphorylation. Measured driving forces [extramitochondrial phosphorylation potential (ΔGATP), membrane potential, and redox states of NADH and cytochromes bH, bL, c1, c, and a,a3] were compared with flux (oxygen consumption) at 37 °C; 840 nM Ca(2+) generated an ∼2-fold increase in VmaxO with no change in ADP affinity (∼43 μM). Force-flow analysis revealed that Ca(2+) activation of VmaxO was distributed throughout the oxidative phosphorylation reaction sequence. Specifically, Ca(2+) increased the conductance of Complex IV (2.3-fold), Complexes I and III (2.2-fold), ATP production/transport (2.4-fold), and fuel transport/dehydrogenases (1.7-fold). These data support the notion that Ca(2+) activates the entire muscle oxidative phosphorylation cascade, while extrapolation of these data to the exercising muscle predicts a significant role of Ca(2+) in maintaining cellular energy homeostasis.n maintaining cellular energy homeostasis.)
Young 2021 J Biol Chem + (Calcium signaling is essential for regulat … Calcium signaling is essential for regulating many biological processes. Endoplasmic reticulum (ER) inositol trisphosphate receptors (IP3R) and the mitochondrial Ca2+ uniporter (MCU) are key proteins that regulate intracellular Ca2+ concentration. Mitochondrial Ca2+ accumulation activates Ca2+-sensitive dehydrogenases of the tricarboxylic acid (TCA) cycle that maintain the biosynthetic and bioenergetics needs of both normal and cancer cells. However, the interplay between calcium signaling and metabolism is not well understood. In this study, we used human cancer cell lines (HEK293, HeLa) with stable knockouts of all three IP3R isoforms (TKO) or MCU to examine metabolic and bioenergetic responses to the chronic loss of cytosolic and/or mitochondrial Ca2+ signaling. Our results show that TKO cells (exhibiting total loss of Ca2+ signaling) are viable, displaying a lower proliferation and oxygen consumption rate, with no significant changes in ATP levels, even when made to rely solely on the TCA cycle for energy production. MCU KO cells also maintained normal ATP levels, but showed increased proliferation, oxygen consumption, and metabolism of both glucose and glutamine. However, MCU KO cells were unable to maintain ATP levels and died when relying solely on the TCA cycle for energy. We conclude that constitutive Ca2+ signaling is dispensable for the bioenergetic needs of both IP3R TKO and MCU KO human cancer cells, likely due to adequate basal glycolytic and TCA cycle flux. However, in MCU KO cells, the higher energy expenditure associated with increased proliferation and oxygen consumption makes these cells more prone to bioenergetic failure under conditions of metabolic stress.roliferation and oxygen consumption makes these cells more prone to bioenergetic failure under conditions of metabolic stress.)
Moon 2016 J Biol Chem + (Calcium-independent phospholipase A2γ (iPL … Calcium-independent phospholipase A2γ (iPLA2γ) is a mitochondrial enzyme that produces lipid second messengers that facilitate opening of the mitochondrial permeability transition pore (mPTP) and contribute to the production of oxidized fatty acids in myocardium. To specifically identify the roles of iPLA2γ in cardiac myocytes, we generated cardiac myocyte-specific iPLA2γ knock-out (CMiPLA2γKO) mice by removing the exon encoding the active site serine (Ser-477). Hearts of CMiPLA2γKO mice exhibited normal hemodynamic function, glycerophospholipid molecular species composition, and normal rates of mitochondrial respiration and ATP production. In contrast, CMiPLA2γKO mice demonstrated attenuated Ca(2+)-induced mPTP opening that could be rapidly restored by the addition of palmitate and substantially reduced production of oxidized polyunsaturated fatty acids (PUFAs). Furthermore, myocardial ischemia/reperfusion (I/R) in CMiPLA2γKO mice (30 min of ischemia followed by 30 min of reperfusion ''in vivo'') dramatically decreased oxidized fatty acid production in the ischemic border zones. Moreover, CMiPLA2γKO mice subjected to 30 min of ischemia followed by 24 h of reperfusion ''in vivo'' developed substantially less cardiac necrosis in the area-at-risk in comparison with their WT littermates. Furthermore, we found that membrane depolarization in murine heart mitochondria was sensitized to Ca(2+) by the presence of oxidized PUFAs. Because mitochondrial membrane depolarization and calcium are known to activate iPLA2γ, these results are consistent with salvage of myocardium after I/R by iPLA2γ loss of function through decreasing mPTP opening, diminishing production of proinflammatory oxidized fatty acids, and attenuating the deleterious effects of abrupt increases in calcium ion on membrane potential during reperfusion.© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.r Biochemistry and Molecular Biology, Inc.)
Chen 2015 Am J Physiol Endocrinol Metab + (Caloric restriction (CR) attenuates age-re … Caloric restriction (CR) attenuates age-related muscle loss. However, the underlying mechanism responsible for this attenuation is not fully understood. This study evaluated the role of energy metabolism in the CR-induced attenuation of muscle loss. The aims of this study were twofold: 1) to evaluate the effect of CR on energy metabolism and determine its relationship with muscle mass, and 2) to determine whether the effects of CR are age dependent. Young and middle-aged rats were randomized into either 40% CR or ''ad libitum'' (AL) diet groups for 14 wk. Major energy-producing pathways in muscles, i.e., glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), were examined. We found that the effects of CR were age dependent. CR improved muscle metabolism and normalized muscle mass in middle-aged animals but not young animals. CR decreased glycolysis and increased the cellular dependency for OXPHOS vs. glycolysis in muscles of middle-aged rats, which was associated with the improvement of normalized muscle mass. The metabolic reprogramming induced by CR was related to modulation of pyruvate metabolism and increased mitochondrial biogenesis. Compared with animals fed AL, middle-aged animals with CR had lower lactate dehydrogenase A content and greater mitochondrial pyruvate carrier content. Markers of mitochondrial biogenesis, including AMPK activation levels and SIRT1 and COX-IV content, also showed increased levels. In conclusion, 14 wk of CR improved muscle metabolism and preserved muscle mass in middle-aged animals but not in young developing animals. CR-attenuated age-related muscle loss is associated with reprogramming of the metabolic pathway from glycolysis to OXPHOS.tabolic pathway from glycolysis to OXPHOS.)
Niemann 2022 Biology (Basel) + (Caloric restriction (CR) extends lifespan … Caloric restriction (CR) extends lifespan in many species, including mammals. CR is cardioprotective in senescent myocardium by correcting pre-existing mitochondrial dysfunction and apoptotic activation. Furthermore, it confers cardioprotection against acute ischemia-reperfusion injury. Here, we investigated the role of AMP-activated protein kinase (AMPK) in mediating the cardioprotective CR effects in failing, postinfarct myocardium.Ligation of the left coronary artery or sham operation was performed in rats and mice. Four weeks after surgery, left ventricular (LV) function was analyzed by echocardiography, and animals were assigned to different feeding groups (control diet or 40% CR, 8 weeks) as matched pairs. The role of AMPK was investigated with an AMPK inhibitor in rats or the use of alpha 2 AMPK knock-out mice.CR resulted in a significant improvement in LV function, compared to postinfarct animals receiving control diet in both species. The improvement in LV function was accompanied by a reduction in serum BNP, decrease in LV proapoptotic activation, and increase in mitochondrial biogenesis in the LV. Inhibition or loss of AMPK prevented most of these changes.The failing, postischemic heart is protected from progressive loss of LV systolic function by CR. AMPK activation is indispensable for these protective effects.ndispensable for these protective effects.)
Boutant 2016 Cell Rep + (Caloric restriction (CR) has been shown to … Caloric restriction (CR) has been shown to prevent the onset of insulin resistance and to delay age-related physiological decline in mammalian organisms. SIRT1, a NAD(+)-dependent deacetylase enzyme, has been suggested to mediate the adaptive responses to CR, leading to the speculation that SIRT1 activation could be therapeutically used as a CR-mimetic strategy. Here, we used a mouse model of moderate SIRT1 overexpression to test whether SIRT1 gain of function could mimic or boost the metabolic benefits induced by every-other-day feeding (EODF). Our results indicate that SIRT1 transgenesis does not affect the ability of EODF to decrease adiposity and improve insulin sensitivity. Transcriptomic analyses revealed that SIRT1 transgenesis and EODF promote very distinct adaptations in individual tissues, some of which can even be metabolically opposite, as in brown adipose tissue. Therefore, whereas SIRT1 overexpression and CR both improve glucose metabolism and insulin sensitivity, the etiologies of these benefits are largely different.Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.shed by Elsevier Inc. All rights reserved.)
Johnson 2016 Diabetes + (Caloric restriction (CR) improves insulin … Caloric restriction (CR) improves insulin sensitivity and reduces the incidence of diabetes in obese individuals. The underlying mechanisms whereby CR improves insulin sensitivity are not clear. We evaluated the effect of 16 weeks of CR on whole-body insulin sensitivity by pancreatic clamp before and after CR in 11 obese participants (BMI = 35 kg/m(2)) compared with 9 matched control subjects (BMI = 34 kg/m(2)). Compared with the control subjects, CR increased the glucose infusion rate needed to maintain euglycemia during hyperinsulinemia, indicating enhancement of peripheral insulin sensitivity. This improvement in insulin sensitivity was not accompanied by changes in skeletal muscle mitochondrial oxidative capacity or oxidant emissions, nor were there changes in skeletal muscle ceramide, diacylglycerol, or amino acid metabolite levels. However, CR lowered insulin-stimulated thioredoxin-interacting protein (TXNIP) levels and enhanced nonoxidative glucose disposal. These results support a role for TXNIP in mediating the improvement in peripheral insulin sensitivity after CR.n peripheral insulin sensitivity after CR.)
Serna 2020 J Bioenerg Biomembr + (Caloric restriction (CR) is widely known t … Caloric restriction (CR) is widely known to increase life span and resistance to different types of injuries in several organisms. We have previously shown that mitochondria from livers or brains of CR animals exhibit higher calcium uptake rates and lower sensitivity to calcium-induced mitochondrial permeability transition (mPT), an event related to the resilient phenotype exhibited by these organs. Given the importance of calcium in metabolic control and cell homeostasis, we aimed here to uncover possible changes in mitochondrial calcium handling, redox balance and bioenergetics in cardiac and skeletal muscle mitochondria in response to six months of CR. Unexpectedly, we found that CR does not alter the susceptibility to mPT in muscle (cardiac or skeletal), nor calcium uptake rates. Despite the lack in changes in calcium transport properties, CR consistently decreased respiration in the presence of ATP synthesis in heart and soleus muscle. In heart, such changes were accompanied by a decrease in respiration in the absence of ATP synthesis, lower maximal respiratory rates and a reduced rate of hydrogen peroxide release. Hydrogen peroxide release was unaltered by CR in skeletal muscle. No changes were observed in inner membrane potentials and respiratory control ratios. Together, these results highlight the tissue-specific bioenergetic and ion transport effects induced by CR, demonstrating that resilience against calcium-induced mPT is not present in all tissues.induced mPT is not present in all tissues.)
Lanza 2012 Cell Metab + (Caloric restriction (CR) mitigates many de … Caloric restriction (CR) mitigates many detrimental effects of aging and prolongs life span. CR has been suggested to increase mitochondrial biogenesis, thereby attenuating age-related declines in mitochondrial function, a concept that is challenged by recent studies. Here we show that lifelong CR in mice prevents age-related loss of mitochondrial oxidative capacity and efficiency, measured in isolated mitochondria and permeabilized muscle fibers. We find that these beneficial effects of CR occur without increasing mitochondrial abundance. Whole-genome expression profiling and large-scale proteomic surveys revealed expression patterns inconsistent with increased mitochondrial biogenesis, which is further supported by lower mitochondrial protein synthesis with CR. We find that CR decreases oxidant emission, increases antioxidant scavenging, and minimizes oxidative damage to DNA and protein. These results demonstrate that CR preserves mitochondrial function by protecting the integrity and function of existing cellular components rather than by increasing mitochondrial biogenesis.Copyright © 2012 Elsevier Inc. All rights reserved. © 2012 Elsevier Inc. All rights reserved.)
Menezes-Filho 2017 Free Radic Biol Med + (Caloric restriction (CR) promotes lifespan … Caloric restriction (CR) promotes lifespan extension and protects against many pathological conditions, including ischemia/reperfusion injury to the brain, heart and kidney. In the liver, ischemia/reperfusion damage is related to excessive mitochondrial Ca2+ accumulation, leading to the mitochondrial permeability transition. Indeed, liver mitochondria isolated from animals maintained on CR for 4 months were protected against permeability transition and capable of taking up Ca2+ at faster rates and in larger quantities. These changes were not related to modifications in mitochondrial respiratory activity, but rather to a higher proportion of ATP relative to ADP in CR liver mitochondria. Accordingly, both depletion of mitochondrial adenine nucleotides and loading mitochondria with exogenous ATP abolished the differences between CR and ad libitum (AL) fed groups. The prevention against permeability transition promoted by CR strongly protected against ''in vivo'' liver damage induced by ischemia/reperfusion. Overall, our results show that CR strongly protects the liver against ischemia/reperfusion and uncover a mechanism for this protection, through a yet undescribed diet-induced change in liver mitochondrial Ca2+ handling related to elevated intramitochondrial ATP.Copyright © 2017 Elsevier Inc. All rights reserved.d intramitochondrial ATP. Copyright © 2017 Elsevier Inc. All rights reserved.)
Amigo 2016 Aging Cell + (Caloric restriction (CR) protects against … Caloric restriction (CR) protects against many cerebral pathological conditions that are associated with excitotoxic damage and calcium overload, although the mechanisms are still poorly understood. Here we show that CR strongly protects against excitotoxic insults ''in vitro'' and ''in vivo'' in a manner associated with significant changes in mitochondrial function. CR increases electron transport chain activity, enhances antioxidant defenses, and favors mitochondrial calcium retention capacity in the brain. These changes are accompanied by a decrease in cyclophilin D activity and acetylation and an increase in Sirt3 expression. This suggests that Sirt3-mediated deacetylation and inhibition of cyclophilin D in CR promote the inhibition of mitochondrial permeability transition, resulting in enhanced mitochondrial calcium retention. Altogether, our results indicate that enhanced mitochondrial calcium retention capacity underlies the beneficial effects of CR against excitotoxic conditions. This protection may explain the many beneficial effects of CR in the aging brain.© 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.tomical Society and John Wiley & Sons Ltd.)
Wang 2023 Nature + (Caloric restriction that promotes weight l … Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake4-7. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL-β-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15-GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction. maintaining energy expenditure in skeletal muscle during caloric restriction.)
Pardo 2018 FASEB J + (Calorie restriction (CR) exerts remarkable … Calorie restriction (CR) exerts remarkable, beneficial effects on glucose homeostasis by mechanisms that are not fully understood. Given the relevance of white adipose tissue (WAT) in glucose homeostasis, we aimed at identifying the main cellular processes regulated in WAT in response to CR in a pathologic context of obesity. For this, a gene-expression profiling study was first conducted in mice fed ''ad libitum'' or subjected to 40% CR. We found that the gene network related to mitochondria was the most highly upregulated in WAT by CR. To study the role that increased mitochondrial biogenesis plays on glucose homeostasis following CR, we generated a mouse model devoid of the coactivators peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1)α and PGC-1β specifically in adipocytes. Our results show that mice lacking PGC-1s in adipocytes are unable to increase mitochondrial biogenesis in WAT upon CR. Despite a blunted induction of mitochondrial biogenesis in response to calorie deprivation, mice lacking adipose PGC-1s still respond to CR by improving their glucose homeostasis. Our study demonstrates that PGC-1 coactivators are major regulators of CR-induced mitochondrial biogenesis in WAT and that increased mitochondrial biogenesis and oxidative function in adipose tissue are not required for the improvement of glucose homeostasis mediated by CR.ent of glucose homeostasis mediated by CR.)
Gnaiger 1990 Biochim Biophys Acta + (Calorimetric and respirometric studies of … Calorimetric and respirometric studies of cultured cells show that both neoplastic and non-neoplastic cell types maintain an anaerobic contribution to their total heat flux. In many mammalian cells this can be explained quantitatively by lactate production observed under fully aerobic conditions. Uncoupling and enhanced futile substrate cycling increase the ratio of heat flux to oxygen flux, the calorimetric-respirometric (CR) ratio. The interpretation of calorimetric and respirometric measurements requires an energy balance approach in which experimentally measured CR ratios are compared with thermochemically derived oxycaloric equivalents. The oxycaloric equivalent is the enthalpy change per mole of oxygen consumed, and equals −470 kJ / mol O2 in the aerobic catabolism of glucose, assuming that catabolism is 100% dissipative (the net efficiency of metabolic heat transformation is zero). CR ratios more negative than −470 kJ / mol O2 have been reported in well-oxygenated cell cultures and are discussed in terms of integrated aerobic and anaerobic metabolism.discussed in terms of integrated aerobic and anaerobic metabolism.)
Targeting Mitochondrial Dysfunction & Toxicity 2015 + (Cambridge Healthtech Institute, Cambridge MA, USA; [http://www.healthtech.com/mitochondrial-targeting Targeting Mitochondrial Dysfunction & Toxicity - Treating Disease and Improving Drug Safety].)
Lin 2020 EBioMedicine + (Canagliflozin (CANA) administration increa … Canagliflozin (CANA) administration increases the risk of lower limb amputation in the clinic. The present study aimed to investigate whether and how CANA interferes with the intracellular physiological processes of bone marrow derived mesenchymal stem cells (BM-MSCs) and its contribution to ischaemic lower limb.The ''in vivo'' blood flow recovery in ischaemic lower limbs following CANA treatment was evaluated. The cellular function of BM-MSCs after CANA treatment were also assessed ''in vitro''. ''In silico'' docking analysis and mutant substitution assay were conducted to confirm the interaction of CANA with glutamate dehydrogenase 1 (GDH1).Following CANA treatment, attenuated angiogenesis and hampered blood flow recovery in the ischaemic region were detected in diabetic and non-diabetic mice, and inhibition of the proliferation and migration of BM-MSCs were also observed. CANA was involved in mitochondrial respiratory malfunction in BM-MSCs and the inhibition of ATP production, cytochrome c release and vessel endothelial growth factor A (VEGFA) secretion, which may contribute to reductions in the tissue repair capacity of BM-MSCs. The detrimental effects of CANA on MSCs result from the inhibition of GDH1 by CANA (evidenced by ''in silico'' docking analysis and H199A-GDH1/N392A-GDH1 mutant substitution).Our work highlights that the inhibition of GDH1 activity by CANA interferes with the metabolic activity of the mitochondria, and this interference deteriorates the retention of and VEGFA secretion by MSCs.Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.ed by Elsevier B.V. All rights reserved.)
Hawley 2016 Diabetes + (Canagliflozin, dapagliflozin, and empaglif … Canagliflozin, dapagliflozin, and empagliflozin, all recently approved for treatment of type 2 diabetes, were derived from the natural product phlorizin. They reduce hyperglycemia by inhibiting glucose reuptake by sodium/glucose cotransporter (SGLT) 2 in the kidney, without affecting intestinal glucose uptake by SGLT1. We now report that canagliflozin also activates AMPK, an effect also seen with phloretin (the aglycone breakdown product of phlorizin), but not to any significant extent with dapagliflozin, empagliflozin, or phlorizin. AMPK activation occurred at canagliflozin concentrations measured in human plasma in clinical trials and was caused by inhibition of Complex I of the respiratory chain, leading to increases in cellular AMP or ADP. Although canagliflozin also inhibited cellular glucose uptake independently of SGLT2, this did not account for AMPK activation. Canagliflozin also inhibited lipid synthesis, an effect that was absent in AMPK knockout cells and that required phosphorylation of acetyl-CoA carboxylase (ACC) 1 and/or ACC2 at the AMPK sites. Oral administration of canagliflozin activated AMPK in mouse liver, although not in muscle, adipose tissue, or spleen. Because phosphorylation of ACC by AMPK is known to lower liver lipid content, these data suggest a potential additional benefit of canagliflozin therapy compared with other SGLT2 inhibitors.© 2016 by the American Diabetes Association.2016 by the American Diabetes Association.)

Abcam 2018 Cambridge UK + (Cancer and Metabolism conference, Cambridge, United Kingdom, 2018)

Kunz 2020 J Biol Chem + (Cancer cachexia is characterized by reduct … Cancer cachexia is characterized by reductions in peripheral lean muscle mass. Prior studies have primarily focused on increased protein breakdown as the driver of cancer-associated muscle wasting. Therapeutic interventions targeting catabolic pathways have, however, largely failed to preserve muscle mass in cachexia, suggesting that other mechanisms might be involved. In pursuit of novel pathways, we used untargeted metabolomics to search for metabolite signatures that may be linked with muscle atrophy. We injected seven-week old C57/BL6 mice with LLC1 tumor cells or vehicle. After 21 days, tumor-bearing mice exhibited reduced body and muscle mass and impaired grip strength compared to controls, which was accompanied by lower synthesis rates of mixed muscle protein and the myofibrillar and sarcoplasmic muscle fractions. Reductions in protein synthesis were accompanied by mitochondrial enlargement and reduced coupling efficiency in tumor-bearing mice. To generate mechanistic insights into impaired protein synthesis, we performed untargeted metabolomic analyses of plasma and muscle and found increased concentrations of two methylarginines, asymmetric dimethylarginine (ADMA) and NG-monomethyl-L-arginine, in tumor-bearing mice compared to control mice. Compared to healthy controls, human cancer patients were also found to have higher levels of ADMA in the skeletal muscle. Treatment of C2C12 myotubes with ADMA impaired protein synthesis and reduced mitochondrial protein quality. These results suggest that increased levels of ADMA and mitochondrial changes may contribute to impaired muscle protein synthesis in cancer cachexia and could point to novel therapeutic targets by which to mitigate cancer cachexia.gets by which to mitigate cancer cachexia.)
Plecita-Hlavata 2015 J Bioenerg Biomembr + (Cancer cell bioenergetics, maintaining mix … Cancer cell bioenergetics, maintaining mixed aerobic glycolysis (Warburg phenotype) and oxidative phosphorylation (OXPHOS), is not fully elucidated. Hypoxia-dependent OXPHOS suppression determines aerobic glycolysis. To elucidate further details, we studied hypoxic adaptation (up to 72 h at 5% oxygen) of hepatocellular carcinoma HepG2 cells. The key regulatory component, hypoxia-inducible factor (HIF)-1α (HIF-1α) was stabilized at 5 h in 5% oxygen for all three studied regimens, i.e. in glycolytic cells at 5 mM or 25 mM glucose, or in aglycemic (OXPHOS) cells when glucose was replaced by galactose. However, the conventional HIF-mediated suppression of respiration was prevented at aglycemia, which correlated with a high proportion of unphosphorylated pyruvate dehydrogenase (PDH) at 5% oxygen. Such a modified HIF response in OXPHOS cells, termed as a non-canonical one, contrasted to conventional respiration suppression down to 45% or 43%, observed in hypoxia-adapted glycolytic cells at 5 mM or 25 mM glucose, respectively. These hypoxic glycolytic cells had normally highly phosphorylated PDH and most likely utilized pyruvate by aminotransferase reaction of glutaminolysis to feed at least suppressed respiration. Also, glycolytic cells were rather resistant towards the staurosporine-induced apoptosis, whereas aglycemic (OXPHOS) HepG2 cells exhibited much higher susceptibility. We conclude that aglycemia modulates the hypoxic HIF signaling toward a non-canonical response that is unable to carry out complete PDH phosphorylation, allowing a high pyruvate input for OXPHOS from the elevated glycolysis, which together with ongoing glutaminolysis maintain a virtually unchanged respiration. Similar OXPHOS revival may explain distinct tumor sensitivity to chemotherapy and other pharmacological interventions.y and other pharmacological interventions.)
De Sales 2018 Molecules + (Cancer cells demand high ATP provisions to … Cancer cells demand high ATP provisions to support proliferation, and targeting of energy metabolism is a good strategy to increase their sensitivity to treatments. In Brazil, wine manufacture is expanding, increasing the amount of pomace that is produced. We determined the phenolic composition and antioxidant properties of a dark skin Grape Pomace Extract and its effects on metabolism and redox state in human hepatocarcinoma HepG2 cells. The material and the methods used represented the industrial process since pomace derived from white wine production and the extract concentrated by pilot plant scale reverse osmosis. Grape pomace extract was rich in polyphenols, mainly anthocyanins, and presented high antioxidant capacity. Short-term metabolic effects, irrespective of any cytotoxicity, involved increased mitochondrial respiration and antioxidant capacity and decreased glycolytic metabolism. Long-term incubation was cytotoxic and cells died by necrosis and GPE was not toxic to non-cancer human fibroblasts. To the best of our knowledge, this is the first report to characterize pomace extract from white wine production from Brazilian winemaking regarding its effects on energy metabolism, suggesting its potential use for pharmaceutical and nutraceutical purposes.pharmaceutical and nutraceutical purposes.)
Bastian 2016 Cancer Lett + (Cancer cells have a unique metabolic profi … Cancer cells have a unique metabolic profile and mitochondria have been shown to play an important role in chemoresistance, tumor progression and metastases. This unique profile can be exploited by mitochondrial-targeted anticancer therapies. A small anticancer molecule, AG311, was previously shown to possess anticancer and antimetastatic activity in two cancer mouse models and to induce mitochondrial depolarization. This study defines the molecular effects of AG311 on the mitochondria to elucidate its observed efficacy. AG311 was found to competitively inhibit complex I activity at the ubiquinone-binding site. Complex I as a target for AG311 was further established by measuring oxygen consumption rate in tumor tissue isolated from AG311-treated mice. Cotreatment of cells and animals with AG311 and dichloroacetate, a pyruvate dehydrogenase kinase inhibitor that increases oxidative metabolism, resulted in synergistic cell kill and reduced tumor growth. The inhibition of mitochondrial oxygen consumption by AG311 was found to reduce HIF-1α stabilization by increasing oxygen tension in hypoxic conditions. Taken together, these results suggest that AG311 at least partially mediates its antitumor effect through inhibition of complex I, which could be exploited in its use as an anticancer agent.Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.Elsevier Ireland Ltd. All rights reserved.)
Begum 2023 WIREs Mech Dis + (Cancer cells have an abnormally high mitoc … Cancer cells have an abnormally high mitochondrial membrane potential (ΔΨm ), which is associated with enhanced invasive properties in vitro and increased metastases in vivo. The mechanisms underlying the abnormal ΔΨm in cancer cells remain unclear. Research on different cell types has shown that ΔΨm is regulated by various intracellular mechanisms such as by mitochondrial inner and outer membrane ion transporters, cytoskeletal elements, and biochemical signaling pathways. On the other hand, the role of extrinsic, tumor microenvironment (TME) derived cues in regulating ΔΨm is not well defined. In this review, we first summarize the existing literature on intercellular mechanisms of ΔΨm regulation, with a focus on cancer cells. We then offer our perspective on the different ways through which the microenvironmental cues such as hypoxia and mechanical stresses may regulate cancer cell ΔΨm .al stresses may regulate cancer cell ΔΨm .)
Verschoor 2010 PLoS One + (Cancer cells predominantly utilize glycoly … Cancer cells predominantly utilize glycolysis for ATP production even in the presence of abundant oxygen, an environment that would normally result in energy production through oxidative phosphorylation. Although the molecular mechanism for this metabolic switch to aerobic glycolysis has not been fully elucidated, it is likely that mitochondrial damage to the electron transport chain and the resulting increased production of reactive oxygen species are significant driving forces. In this study, we have investigated the role of the transcription factor Ets-1 in the regulation of mitochondrial function and metabolism. Ets-1 was over-expressed using a stably-incorporated tetracycline-inducible expression vector in the ovarian cancer cell line 2008, which does not express detectable basal levels of Ets-1 protein. Microarray analysis of the effects of Ets-1 over-expression in these ovarian cancer cells shows that Ets-1 up-regulates key enzymes involved in glycolysis and associated feeder pathways, fatty acid metabolism, and antioxidant defense. In contrast, Ets-1 down-regulates genes involved in the citric acid cycle, electron transport chain, and mitochondrial proteins. At the functional level, we have found that Ets-1 expression is directly correlated with cellular oxygen consumption whereby increased expression causes decreased oxygen consumption. Ets-1 over-expression also caused increased sensitivity to glycolytic inhibitors, as well as growth inhibition in a glucose-depleted culture environment. Collectively our findings demonstrate that Ets-1 is involved in the regulation of cellular metabolism and response to oxidative stress in ovarian cancer cells. oxidative stress in ovarian cancer cells.)
Ma 2018 Cancer Lett + (Cancer cells undergo metabolic reprogrammi … Cancer cells undergo metabolic reprogramming such as enhanced aerobic glycolysis, mutations in the tricarboxylic acid cycle enzymes, and upregulation of de novo lipid synthesis and glutaminolysis. These alterations are pivotal to the development and maintenance of the malignant phenotype of cancer cells in unfavorable tumor microenvironment or metastatic sites. Although mitochondrial fatty acid β-oxidation (FAO) is a primary bioenergetic source, it has not been generally recognized as part of the metabolic landscape of cancer. The last few years, however, have seen a dramatic change in the view of cancer relevance of the FAO pathway. Many recent studies have provided significant evidence to support a “lipolytic phenotype” of cancer. FAO, like other well-defined metabolic pathways involved in cancer, is dysregulated in diverse human malignancies. Cancer cells rely on FAO for proliferation, survival, stemness, drug resistance, and metastatic progression. FAO is also reprogrammed in cancer-associated immune and other host cells, which may contribute to immune suppression and tumor-promoting microenvironment. This article reviews and puts into context our current understanding of multi-faceted roles of FAO in oncogenesis as well as anti-cancer therapeutic opportunities posed by the FAO pathway.ic opportunities posed by the FAO pathway.)
Bajzikova 2019 Cell Metab + (Cancer cells without mitochondrial DNA (mt … Cancer cells without mitochondrial DNA (mtDNA) do not form tumors unless they reconstitute oxidative phosphorylation (OXPHOS) by mitochondria acquired from host stroma. To understand why functional respiration is crucial for tumorigenesis, we used time-resolved analysis of tumor formation by mtDNA-depleted cells and genetic manipulations of OXPHOS. We show that pyrimidine biosynthesis dependent on respiration-linked dihydroorotate dehydrogenase (DHODH) is required to overcome cell-cycle arrest, while mitochondrial ATP generation is dispensable for tumorigenesis. Latent DHODH in mtDNA-deficient cells is fully activated with restoration of complex III/IV activity and coenzyme Q redox-cycling after mitochondrial transfer, or by introduction of an alternative oxidase. Further, deletion of DHODH interferes with tumor formation in cells with fully functional OXPHOS, while disruption of mitochondrial ATP synthase has little effect. Our results show that DHODH-driven pyrimidine biosynthesis is an essential pathway linking respiration to tumorigenesis, pointing to inhibitors of DHODH as potential anti-cancer agents. of DHODH as potential anti-cancer agents.)
Gaude 2014 Cancer Metab + (Cancer is a heterogeneous set of diseases … Cancer is a heterogeneous set of diseases characterized by different molecular and cellular features. Over the past decades, researchers have attempted to grasp the complexity of cancer by mapping the genetic aberrations associated with it. In these efforts, the contribution of mitochondria to the pathogenesis of cancer has tended to be neglected. However, more recently, a growing body of evidence suggests that mitochondria play a key role in cancer. In fact, dysfunctional mitochondria not only contribute to the metabolic reprogramming of cancer cells but they also modulate a plethora of cellular processes involved in tumorigenesis. In this review, we describe the link between mutations to mitochondrial enzymes and tumor formation. We also discuss the hypothesis that mutations to mitochondrial and nuclear DNA could cooperate to promote the survival of cancer cells in an evolving metabolic landscape. cells in an evolving metabolic landscape.)
Macasoi 2020 Oncol Rep + (Cancer remains a major health problem worl … Cancer remains a major health problem worldwide due to its high mortality rate. New therapeutic options highlight the importance of discovering new compounds that target the tumor microenvironment, interrupt angiogenesis and act selectively. The present study assessed the antitumor effect and investigated the mechanism of action of a rhodamine B‑conjugated oleanolic acid derivative (RhodOA). Consequently, the compound was tested on different human tumor cell lines (A375 melanoma, A549 lung adenocarcinoma and MDA‑MB‑231 breast adenocarcinoma) and on a non‑tumor cell line HaCaT human keratinocyte. RhodOA produced a dose‑dependent decrease in tumor cell viability especially in the melanoma cells while affecting the keratinocytes less. In melanoma cells, RhodOA reduced cell migration and produced condensation of cell nuclei and of actin fibers. Furthermore, an impairment in melanoma cell mitochondrial function was observed, while the mitochondrial function of keratinocytes was left intact. In the ''in ovo'' chorioallantoic membrane model, RhodOA elicited antiangiogenic effect, without showing irritation effect on the membrane. The study provides information on the selective antitumor effect of the derivative and its ability to inhibit cellular respiration, therefore RhodOA can be classified as ‘MITOCAN’.ore RhodOA can be classified as ‘MITOCAN’.)
Lu 2023 Explor Res Hypothesis Med + (Cancer research has made a magnificent pro … Cancer research has made a magnificent progress in past decades with an advancement of molecular biology. However, the mechanisms of cancer transformation are still not fully revealed. Thus, we must think about if there are some unknown factors playing a causative role in the cancer formation. Mitochondrial complex I oxidizes NADH to NAD+ and reduces ubiquinone to ubiquinol, regenerated NAD+ keeping pyruvate dehydrogenase and Krebs cycle function. Hydrogenases are widespread in nature, they occur in bacteria, archaea, and some eukarya. It is unknown whether hydrogenase activity exists in human mitochondria. The complex I shares a last common ancestor with hydrogenases, and is closely related with hydrogenase in sequence and modular structure. The hydrogenase activity has been observed recently in complex I of higher plants. Based on these observations, I propose a hypothesis that mitochondrial complex I in human may also retain the hydrogenase activity. The hypothetical hydrogenase activity could release excessive reducing equivalents of NADH from electron transport chain when a cell is in hypoxia, decreased oxidative phosphorylation or a low ATP demand. Loss of the hydrogenase activity may result in aerobic glycolysis, activation of pentose phosphate pathway, elevated lipid synthesis, and activations of oncoproteins via acetylation, all of these alterations lead to cell proliferations and cancer transformation. Reducing mitochondrial NADH/NAD+ ratio or recovering the hydrogenase activity would reverse the cell transformation.ity would reverse the cell transformation.)
Shen 2021 Cells + (Cancer stem cells (CSCs) are heterogeneous … Cancer stem cells (CSCs) are heterogeneous cells with stem cell-like properties that are responsible for therapeutic resistance, recurrence, and metastasis, and are the major cause for cancer treatment failure. Since CSCs have distinct metabolic characteristics that plays an important role in cancer development and progression, targeting metabolic pathways of CSCs appears to be a promising therapeutic approach for cancer treatment. Here we classify and discuss the unique metabolisms that CSCs rely on for energy production and survival, including mitochondrial respiration, glycolysis, glutaminolysis, and fatty acid metabolism. Because of metabolic plasticity, CSCs can switch between these metabolisms to acquire energy for tumor progression in different microenvironments compare to the rest of tumor bulk. Thus, we highlight the specific conditions and factors that promote or suppress CSCs properties to portray distinct metabolic phenotypes that attribute to CSCs in common cancers. Identification and characterization of the features in these metabolisms can offer new anticancer opportunities and improve the prognosis of cancer. However, the therapeutic window of metabolic inhibitors used alone or in combination may be rather narrow due to cytotoxicity to normal cells. In this review, we present current findings of potential targets in these four metabolic pathways for the development of more effective and alternative strategies to eradicate CSCs and treat cancer more effectively in the future.eat cancer more effectively in the future.)
Petruzzelli 2014 Cell Metab + (Cancer-associated cachexia (CAC) is a wast … Cancer-associated cachexia (CAC) is a wasting syndrome characterized by systemic inflammation, body weight loss, atrophy of white adipose tissue (WAT) and skeletal muscle. Limited therapeutic options are available and the underlying mechanisms are poorly defined. Here we show that a phenotypic switch from WAT to brown fat, a phenomenon termed WAT browning, takes place in the initial stages of CAC, before skeletal muscle atrophy. WAT browning is associated with increased expression of uncoupling protein 1 (UCP1), which uncouples mitochondrial respiration toward thermogenesis instead of ATP synthesis, leading to increased lipid mobilization and energy expenditure in cachectic mice. Chronic inflammation and the cytokine interleukin-6 increase UCP1 expression in WAT, and treatments that reduce inflammation or β-adrenergic blockade reduce WAT browning and ameliorate the severity of cachexia. Importantly, UCP1 staining is observed in WAT from CAC patients. Thus, inhibition of WAT browning represents a promising approach to ameliorate cachexia in cancer patients.to ameliorate cachexia in cancer patients.)
Cruz 2020 Cancers (Basel) + (Cancer-cachexia induces a variety of metab … Cancer-cachexia induces a variety of metabolic disorders, including skeletal muscle imbalance. Alternative therapy, as nutritional supplementation with leucine, shows a modulatory effect over tumour damage ''in vivo'' and ''in vitro''. Adult rats distributed into Control (C), Walker tumour-bearing (W), control fed a leucine-rich diet (L), and tumour-bearing fed a leucine-rich diet (WL) groups had the gastrocnemius muscle metabolomic and proteomic assays performed in parallel to ''in vitro'' assays. W group presented an affected muscle metabolomic and proteomic profile mainly related to energy generation and carbohydrates catabolic processes, but leucine-supplemented group (WL) recovered the energy production. ''In vitro'' assay showed that cell proliferation, mitochondria number and oxygen consumption were higher under leucine effect than the tumour influence. Muscle proteomics results showed that the main affected cell component was mitochondria, leading to an impacted energy generation, including impairment in proteins of the tricarboxylic cycle and carbohydrates catabolic processes, which were modulated and improved by leucine treatment. In summary, we showed a beneficial effect of leucine upon mitochondria, providing information about the muscle glycolytic pathways used by this amino acid, where it can be associated with the preservation of morphometric parameters and consequent protection against the effects of cachexia.rotection against the effects of cachexia.)
Chang 2018 Life Sciences Meeting 2018 Innsbruck AT + (Cancers are characterized by a high metabo … Cancers are characterized by a high metabolic plasticity resulting from mutations and the selection of metabolic phenotypes. Metabolic transformations involve mitochondrial adaptation or mitochondrial dysfunction. Metabolism and mitochondria have become focal targets for anticancer therapy. In the progression of tumor, cancer cells upregulate glucose uptake and glycolysis. The different environmental and intracellular pH due to the metabolic reprogramming can change the behavior of the cells. Therefore, we compared the effects of pH on mitochondrial respiration and H2O2 production in different cell lines. We measured respiration and H2O2 production in permeabilized human embryonic kidney cells (HEK239T), human gingival fibroblasts (HGF) and human oral squamous carcinoma cancer cells (SCC25) in the pH range from 6.6 – 7.5 using high-resolution respirometry including the Amplex UltraRed assay. We used substrate-uncoupler-inhibitor titration protocols to access mitochondrial respiration in different coupling and pathway control states, activating the succinate (S)-, NADH- (N) and fatty acid (F)- pathways separately or in combination.With increasing pH, H2O2 flux decreased in HEK239T cells in the S- and N-pathways, while O2 flux was significantly increased. A similar result was observed in HGF. Conversely, the SCC25 cells showed an opposite trend. In these cancer cells, electron transfer pathways and Complex IV activity were depressed at high pH. HGF and SCC25 showed a higher sensitivity to intracellular pH compared to HEK293T cells.SCC25 cancer cells showed a response of respiration to changes in pH that was opposite compared to normal HGF and HEK293T cells. The sensitivity of mitochondrial respiration to modulations of intracellular pH may have implications on chemotherapy sensitivity. Therefore, the experimental design evaluated in the present study will be applied in radioresistant SCC25 cells and radiochemotherapy sensitive SCC-090 cells.gn evaluated in the present study will be applied in radioresistant SCC25 cells and radiochemotherapy sensitive SCC-090 cells.)
Copsey 2021 Sci Rep + (Candidemia caused by ''Candida'' spp. is a … Candidemia caused by ''Candida'' spp. is a serious threat in hospital settings being a major cause of acquired infection and death and a possible contributor to Covid-19 mortality. Candidemia incidence has been rising worldwide following increases in fungicide-resistant pathogens highlighting the need for more effective antifungal agents with novel modes of action. The membrane-bound enzyme alternative oxidase (AOX) promotes fungicide resistance and is absent in humans making it a desirable therapeutic target. However, the lipophilic nature of the AOX substrate (ubiquinol-10) has hindered its kinetic characterisation in physiologically-relevant conditions. Here, we present the purification and expression of recombinant AOXs from ''C. albicans'' and ''C. auris'' in a self-assembled proteoliposome (PL) system. Kinetic parameters (Km and Vmax) with respect to ubiquinol-10 have been determined. The PL system has also been employed in dose-response assays with novel AOX inhibitors. Such information is critical for the future development of novel treatments for Candidemia.© 2021. The Author(s). treatments for Candidemia. © 2021. The Author(s). )
Homsani 2013 Int J High Dilution Res + (Candidiasis is an opportunist infection, c … Candidiasis is an opportunist infection, caused by yeast of the genus ''Candida''. It usually affects immunossupressed and critical patients, and may progress to a systemic infection with high morbidity and mortality rates. ''Candida albicans'' is its most common causing agent. The yeast adhesion to the host epithelial cells is a great stimulator for the hyphae formation, which is the invasive form of this fungal[1]. Nosodes are homeopathic medicines employed with great success in the clinical treatment of these infections and it is prepared from organic products chemically undefined[2]. Living nosodes RC are prepared from the etiologic agent in integrity state and current studies demonstrate their therapeutic potential[3,4].To evaluate possible alterations induced by RC-type ''C. albicans'' nosodes in cellular respiration and in the adhesion rates of Candida albicans to MA104 cells. RC-type ''Candida albicans'' nosodes were prepared according to the homeopathic pharmacopeia; one part of ''C. albicans'' suspension (108 cell/ml) was diluted in 9 parts of sterile distilled water and submitted to 100 mechanical successions. This sample was subjected to mechanical sucussions 100, leading to 1x. This procedure was repeated successively until 12x and 30x. ''C. albicans'' adhesion rate quantification was performed by flow cytometry after treating MA104 cells for 1, 18 and 40 days with 10% of ''Candida'' RC 12x and 30x. Variations in the respiration parameters of Ma104 cells treated with nosodes for 2 and 4 days were evaluated by high-resolution respirometry[5]. Several experimental conditions were compared to their respective control (cells treated with dinamized and not dinamized sterile distilled water).A decrease in adherence rates, around 20%, was detected when MA104 cells were treated for 18 days with a tendency to decrease fluorescence intensity in all treatments. In addition, treatment with nosodes decreased the MA104 cells respiratory capacity.Results indicate that nosodes modify both the yeasts adhesion rate and maximum respiratory capacity; it is still not possible to say whether there is a direct correlation between these cellular alterations.lation between these cellular alterations.)
Fisar 2014 Toxicol Lett + (Cannabinoids exert various biological effe … Cannabinoids exert various biological effects that are either receptor-mediated or independent of receptor signaling. Mitochondrial effects of cannabinoids were interpreted either as non-receptor-mediated alteration of mitochondrial membranes, or as indirect consequences of activation of plasma membrane type 1 cannabinoid receptors (CB1). Recently, CB1 receptors were confirmed to be localized to the membranes of neuronal mitochondria, where their activation directly regulates respiration and energy production. Here, we performed in-depth analysis of cannabinoid-induced changes of mitochondrial respiration using both an antagonist/inverse agonist of CB1 receptors, AM251 and the cannabinoid receptor agonists, Δ9-tetrahydrocannabinol (THC), cannabidiol, anandamide, and WIN 55,212-2. Relationships were determined between cannabinoid concentration and respiratory rate driven by substrates of complex I, II or IV in pig brain mitochondria. Either full or partial inhibition of respiratory rate was found for the tested drugs, with an IC50 in the micromolar range, which verified the significant role of non-receptor-mediated mechanism in inhibiting mitochondrial respiration. Effect of stepwise application of THC and AM251 evidenced protective role of AM251 and corroborated the participation of CB1 receptor activation in the inhibition of mitochondrial respiration. We proposed a model, which includes both receptor- and non-receptor-mediated mechanisms of cannabinoid action on mitochondrial respiration. This model explains both the inhibitory effect of cannabinoids and the protective effect of the CB1 receptor inverse agonist.th the inhibitory effect of cannabinoids and the protective effect of the CB1 receptor inverse agonist.)
Haney 2023 Nat Med + (Cannabis use disorder (CUD) is widespread, … Cannabis use disorder (CUD) is widespread, and there is no pharmacotherapy to facilitate its treatment. AEF0117, the first of a new pharmacological class, is a signaling-specific inhibitor of the cannabinoid receptor 1 (CB1-SSi). AEF0117 selectively inhibits a subset of intracellular effects resulting from Δ9-tetrahydrocannabinol (THC) binding without modifying behavior per se. In mice and non-human primates, AEF0117 decreased cannabinoid self-administration and THC-related behavioral impairment without producing significant adverse effects. In single-ascending-dose (0.2 mg, 0.6 mg, 2 mg and 6 mg; n = 40) and multiple-ascending-dose (0.6 mg, 2 mg and 6 mg; n = 24) phase 1 trials, healthy volunteers were randomized to ascending-dose cohorts (n = 8 per cohort; 6:2 AEF0117 to placebo randomization). In both studies, AEF0117 was safe and well tolerated (primary outcome measurements). In a double-blind, placebo-controlled, crossover phase 2a trial, volunteers with CUD were randomized to two ascending-dose cohorts (0.06 mg, n = 14; 1 mg, n = 15). AEF0117 significantly reduced cannabis' positive subjective effects (primary outcome measurement, assessed by visual analog scales) by 19% (0.06 mg) and 38% (1 mg) compared to placebo (P < 0.04). AEF0117 (1 mg) also reduced cannabis self-administration (P < 0.05). In volunteers with CUD, AEF0117 was well tolerated and did not precipitate cannabis withdrawal. These data suggest that AEF0117 is a safe and potentially efficacious treatment for CUD.e and potentially efficacious treatment for CUD.)
Mishmar 2015 Abstract MiP2015 + (Canonical RNA-DNA-Differences (RDDs), i.e. … Canonical RNA-DNA-Differences (RDDs), i.e. A-to-G and C-to-U, are important for mammalian sequence diversity. However, non-canonical RDDs have been questioned. Recently, we identified both canonical and non-canonical RDDs (A-to-U and A-to-G) in human mitochondrial 16S rRNA position 947, and suggested that they echo RNA modification. Here, using mass spectrometry and primer extension of 16S rRNA transcripts in human TRMT61B-silenced cells, we show that the RDDs reflect a 1-methyladenosine (m1A) modification. Since these 16S rRNA RDDs were found in all tested human mitochondrial genomes (mtDNAs, ~10,000) and tissues, as well as in 90% of all available vertebrates (''N''>1700), the m1A modification is likely important. Moreover, the m1A alters a bacteria-to-human structurally conserved interface between the small and large mitoribosomal subunits. However, this mtDNA base is a thymine in 10% of the vertebrates, and guanine in most (95%) bacteria (''N''>1300), suggesting functional evolutionary alternatives. Since human mtDNA cannot be modified ''in vivo'', we tested this hypothesis in mutant ''Escherichia coli''. Strikingly, bacterial strains with the mtDNA base (adenine) had impaired protein synthesis and growth as compared to strains with a thymine or a guanine. Modeling m1A, thymine or guanine in the mitoribosome, demonstrated stabilized structure, in contrast to the mtDNA base (adenine). Hence, either 16S rRNA m1A modification, or thymine or guanine in the DNA, are evolutionary alternatives that stabilize mitoribosomes for proper mitochondrial translation. Furthermore, our findings offer a testable model for the occurrence of non-canonical RDDs throughout the human genome. non-canonical RDDs throughout the human genome.)
Messer 2004 Am J Physiol Cell Physiol + (Carbohydrate depletion precipitates fatigu … Carbohydrate depletion precipitates fatigue in skeletal muscle, but, because pyruvate provides both acetyl-CoA for mainline oxidation and anaplerotic carbon to the citric acid cycle (TCA), the mechanism remains obscure. Thus pyruvate and TCA kinetic parameters were independently quantified in mitochondria isolated from rat mixed skeletal muscle. Mitochondrial oxygen consumption rate (Jo) was measured polarographically while either pyruvate or malate was added stepwise in the presence of a saturating concentration of the other substrate. These substrate titrations were carried out across a physiological range of fixed extramitochondrial ATP free energy states (DeltaGP), established with a creatine kinase energy clamp, and also at saturating [ADP]. The apparent Km,malate for mitochondrial Jo ranged from 21 to 32 microM, and the apparent Km,pyruvate ranged from 12 to 26 microM, with both substrate Km values increasing as DeltaGP declined. Vmax for both substrates also increased as DeltaGP fell, reflecting thermodynamic control of Jo. Reported in vivo skeletal muscle [malate] are >10-fold greater than the Km,malate determined in this study. In marked contrast, the K(m,pyruvate) determined is near the [pyruvate] reported in muscle approaching exhaustion associated with glycogen depletion. When data were evaluated in the context of a linear thermodynamic force-flow (DeltaGP-Jo) relationship, the DeltaGP-Jo slope was essentially insensitive to changes in [malate] in the range observed in vivo but decreased markedly with declining [pyruvate] across the physiological range. Mitochondrial respiration is particularly sensitive to variations in [pyruvate] in the physiological range. In contrast, physiological [malate] exerts very little, if any, influence on mitochondrial pyruvate oxidation measured in vitro.ondrial pyruvate oxidation measured in vitro.)
Della Noce 2022 J Biol Chem + (Carbohydrate metabolism not only functions … Carbohydrate metabolism not only functions in supplying cellular energy but also has an important role in maintaining physiological homeostasis and in preventing oxidative damage caused by reactive oxygen species. Previously, we showed that arthropod embryonic cell lines have high tolerance to H2O2 exposure. Here, we describe that ''Rhipicephalus microplus'' tick embryonic cell line (BME26) employs an adaptive glucose metabolism mechanism that confers tolerance to hydrogen peroxide at concentrations too high for other organisms. This adaptive mechanism sustained by glucose metabolism remodeling promotes cell survival and redox balance in BME26 cell line after millimolar H2O2 exposure. The present work shows that this tick cell line could tolerate high H2O2 concentrations by initiating a carbohydrate-related adaptive response. We demonstrate that gluconeogenesis was induced as a compensation strategy that involved, among other molecules, the metabolic enzymes NADP-ICDH, G6PDH, and PEPCK. We also found that this phenomenon was coupled to glycogen accumulation and glucose uptake, supporting the pentose phosphate pathway to sustain NADPH production and leading to cell survival and proliferation. Our findings suggest that the described response is not atypical, being also observed in cancer cells, which highlights the importance of this model to all proliferative cells. We propose that these results will be useful in generating basic biological information to support the development of new strategies for disease treatment and parasite control.ic biological information to support the development of new strategies for disease treatment and parasite control.)
Gnaiger 1984 Oecologia + (Carbohydrate, lipid, and protein compositi … Carbohydrate, lipid, and protein compositions are stoichiometrically related to organic CHN (carbon, hydrogen, nitrogen) contents. Elemental CHN analyses of total biomass and ash, therefore, provide a basis for the calculation of proximate biochemical composition and bomb caloric value. The classical nitrogen to protein conversion factor (6.25) should be replaced by 5.8±0.13. A linear relation exists between the mass fraction of non-protein carbon and the carbohydrate and lipid content. Residual water in dry organic matter can be estimated with the additional information derived from hydrogen measurements. The stoichiometric CHN method and direct biochemical analysis agreed within 10% of ash-free dry biomass (for muscle, liver and fat tissue of silver carp; gut contents composed of detritus and algae; commercial fish food). The detrital material, however, had to be corrected for non-protein nitrogen. A linear relationship between bomb caloric value and organic carbon fractions was derived on the basis of thermodynamic and stoichiometric principles, in agreement with experimental data published for bacteria, algae, protozoa and invertebrates. The highly automatic stoichiometric CHN method for the separation of nutrient contents in biomass extends existing ecophysiological concepts for the construction of balanced carbon and nitrogen, as well as biochemical and energy budgets.as well as biochemical and energy budgets.)
Kaczara 2020 6th EU-Cardioprotection Meeting Riga + (Carbon monoxide (CO) inhibits platelet agg … Carbon monoxide (CO) inhibits platelet aggregation, but the mechanism involved has not been defined. We investigated a possible involvement of bioenergetics in anti-platelet effects of CO.The effects of CO-releasing molecule CORM-A1 on human platelets aggregation, bioenergetics and metabolism were analysed using, respectively, a dual channel aggregometer, Seahorse XFe technique and liquid chromatography tandem-mass spectrometry (LC-MS/MS)-based metabolomics.CORM-A1-induced inhibition of platelet aggregation was accompanied by inhibition of mitochondrial respiration and glycolysis. The effects of CORM-A1 on mitochondrial respiration were proved by a decrease in the concentration of tricarboxylic acid cycle intermediates and oxidized nicotinamide adenine dinucleotide (NAD+), consistent with the inhibition of oxidative phosphorylation. The CORM-A1-induced inhibition of glycolysis was associated with an increase in concentrations of proximal (before glyceraldehyde-3-phosphate dehydrogenase (GAPDH) ), but not distal glycolysis metabolites, implying that CO delayed glycolysis at the level of GAPDH, however GAPDH activity was unaffected by CO. Furthermore, in the presence of exogenous pyruvate the CORM-A1-induced effects on platelet aggregation and glycolysis were abolished, and restored after the inhibition of lactate dehydrogenase, which enables cytosolic NAD+ regeneration, suggesting that glycolysis inhibition resulted from NAD+ depletion.The anti-platelet effect of CO is mediated by the simultaneous inhibition of oxidative phosphorylation and glycolysis by the inhibition of cytochrome c oxidase and depletion of NAD+, respectively.bition of cytochrome c oxidase and depletion of NAD+, respectively.)
Jang 2017 Clin Toxicol (Phila) + (Carbon monoxide (CO) is a colorless and od … Carbon monoxide (CO) is a colorless and odorless gas responsible for poisoning mortality and morbidity in the United States. At this time, there is no reliable method to predict the severity of poisoning or clinical prognosis following CO exposure. Whole blood cells, such as peripheral blood mononuclear cells (PBMCs) and platelets, have been explored for their potential use to act as sensitive biomarkers for mitochondrial dysfunction which may have a role in CO poisoning.The objective of this study was to measure mitochondrial respiration using intact cells obtained from patients exposed to CO as a potential biomarker for mitochondrial inhibition with results that can be obtained in a time frame useful for guiding clinical care. This was a prospective, observational pilot study performed from July 2015 to July 2016 at a single academic tertiary care center that is the location of the region's only multi chamber hyperbaric.Clinical characteristics, patient demographics, mitochondrial respiration and outcomes were recorded.There were 7 patients enrolled with a mean COHb level 26.8 ± 10 and with a mean lactate of 1.1 ± 0.4 mmol/L. All 7 CO exposures were related to heat generators used during winter months with two deaths. There was a positive correlation between maximal respiration and COHb levels with both high maximal respiration and high spare respiratory capacity correlating with a high COHb level. There was a subset of PBMCs (''n'' = 4) that were analyzed for Complex IV (cytochrome c oxidase) activity.In this pilot study, measurements can be performed in an appropriate timeline for clinical care with potential to serve as a prognostic marker. Further work is necessary to develop high-resolution respirometry as a clinical tool for assessing the severity of illness and guiding therapy.e severity of illness and guiding therapy.)