Avram Vlad F

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COST Action CA15203 (2016-2021): MitoEAGLE
Evolution-Age-Gender-Lifestyle-Environment: mitochondrial fitness mapping

Avram Vlad F

MitoPedia topics: MitoPedia topic::EAGLE 

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Name	Has lastname::Avram Has firstname::Vlad Florian, Has title::University assistent
Institution	[[Has institution:: Department of Functional Sciences - Pathophysiology, Faculty of Medicine, "Victor Babeș” University of Medicine and Pharmacy, RO]]
Address	Has address::Eftimie Murgu square, number 2, Has area code::300041
City	In city::Timisoara
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Country	In country::Romania
Email	Has mailaddress::[email protected]
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MitoEAGLE Short-Term Scientific Mission

• • • • STSM Grant Period 4

Work Plan summary

1.Aim and motivation: explain the scientific and/or other motivation for the STSM and what outcomes you aim to accomplish with the STSM. Statins are currently the first-line therapeutic agents in the treatment of most cardio-metabolic afflictions but there are very few studies addressing their effect on platelet respiratory function. Statin- induced mitochondrial dysfunction has been reported as a pathomechanism for the one of the most common side-effect of statins, i.e. myopathy.

Studies on both muscle cells and platelets have shown that mitochondrial respiration is reduced in the presence of certain statins via direct inhibition of complex I. The resulting disruption of cellular bioenergetics may be the cause of the adverse effects associated with statin treatment.

Platelet respirometry has been recently recognized as an adequate predictive model of mitochondrial dysfunction induced by metabolic stress. During the previous STSM at the Mitochondrial Medicine Unit from the University of Lund, Sweden I have started to investigate the toxicity of statins on NADH-dependent platelet respiration and its reversibility by the permeable succinate.

The specific aim of the STSM is to assess whether the statins-induced mitochondrial changes might be mediated via an impairment of the metabolic pathways above the NADH-linked respiration. This will lead to a better understanding of the underlying mechanisms of their side-effects as a continuation of the work started in the previous STSM.

2.Proposed contribution to the scientific objectives of the Action. This mobility will contribute to the scientific objectives of the Working Group 4 (MITO EAGLE data repository for blood cells) in order to provide the continuation of cooperation between our institutions in the emerging field of blood cell respirometry.

The techniques I will learn during this STSM will be further applied in the home institution during my doctoral studies and will allow us to carry on in the future parallel experiments and jointly publish the results under the umbrella of the MITO-EAGLE COST Action. Specifically, the STSM mobility will contribute to the scientific objectives of the Working Group 4 (MITO EAGLE data repository for blood cells), as shown by our communications/posters in the past year.

3. Techniques: pls detail what techniques or equipment you may learn to use. As statins clearly inhibit complex I activity, I will learn to measure the complex I activity in platelets to further understand the nature of statin-induced mitochondrial dysfunction. Also, I plan to learn to assess the citrate synthase activity as a second technique.

The Oxygraph-2K (Oroboros, AT) will be used to assess the respirometry protocol aimed at assessing whether the NADH-linked respiration is the only one affected by statins or if a pathway above this reaction may also contribute to the statin-induced mitochondrial dysfunction.

4. Planning- detail the steps you will take to achieve your proposed aim.

1. Apply the experimental protocol established in the previous STSM to evaluate whether statins affect NADH-linked respiration or a pathway above this reaction (and the reversibility in the presence of permeable succinate) and continue to investigate it when back.

2. Learn the citrate synthase assay and the complex I activity assessment in platelets in order to apply them during my doctoral studies in my home institution.

• • • • STSM Grant Period 3

Work Plan summary

Summary We currently face a globally evolving epidemic of obesity that is intimately linked with the occurence of type 2 diabetes mellitus in both adults and children, hence the term ”diabesity”. Mitochondrial dysfunction is a wellrecognized pathomechanism in metabolic diseases that plays a key role in disease progression. Blood-based bioenergetic profiling has emerged as potential indicator of systemic mitochondrial health. In particular, platelets are nowadays recognized as early predictive markers of mitochondrial dysfunction induced by metabolic stress. Contradictory data are available in the literature with respect to the changes in platelet respiratory capacity in patients with diabetes and metabolic syndrome, respectively. Statins are currently the first line therapeutic agents in the treatment of most cardio-metabolic afflictions but there are no studies addressing their effect on platelet respiration. Characterization of mitochondrial dys/function in platelets as well as the effects of long-term therapy in the setting of metabolic diseases is clearly warranted. Background to the STSM Obesity is a a serious health concern whose prevalence and severity have been constantly rising worldwide in both children and adult population. The global threat of obesity epidemic is related to the high risk of multiple comorbidities, in particular metabolic syndrome and type 2 diabetes mellitus, hence the term ”diabesity” with a the long term negative economic burden. Mitochondrial dysfunction is a well-recognized pathomechanism in metabolic diseases that plays a key role in disease progression. Blood-based bioenergetic profiling has emerged as potential indicator of systemic mitochondrial health. Early detection of mitochondrial dysfunction in peripheral blood cells as putative biomarker in cardiometabolic diseases is currently highly investigated. Recent studies reported the presence of mitochondrial dysfunction in peripheral blood cells of type 2 diabetic patients but not in patients with metabolic syndrome. Statins are currently the first line therapeutic agents in the treatment of most cardio-metabolic afflictions but there are no studies addressing their effect on platelet respiratory function. Specific Aims of the STSM The specific aim of the STSM is to acquire the technical skills in analyzing platelet mitochondrial (dys)function by means of high-resolution respirometry in order to further characterize during his doctoral studies the changes that occur in diabetic and non-diabetic patients treated or nontreated with statins. This mobility will contribute to the scientific objectives of the Working Group 4 (MitoEAGLE data repository for blood cells) and will represent the starting point for future cooperation between our institutions in the emerging field of blood cell respirometry. Workplan elevance of the collaboration (why this project should require a visit to the host institution) The techniques I will learn during this STSM will be further applied in the home institution during my doctoral studies and will allow us to carry on in the future parallel experiments and jointly publish the results under the umbrella of the MitoEAGLE COST Action. Specifically, the STSM mobility will contribute to the scientific objectives of the Working Group 4 (MITO EAGLE data repository for blood cells), References 1. Sjovall F, Ehinger JK, Marelsson SE, Morota S, Frostner EA, Uchino H, et al. Mitochondrial respiration in human viable platelets--methodology and influence of gender, age and storage. Mitochondrion. 2013 Jan;13(1):7-14. 2. Piel S, Ehinger JK, Elmer E, Hansson MJ. Metformin induces lactate production in peripheral blood mononuclear cells and platelets through specific mitochondrial complex I inhibition. Acta physiologica. 2015 Jan;213(1):171-80. 3. Hartman ML, Shirihai OS, Holbrook M, Xu G, Kocherla M, Shah A, Fetterman JL, Kluge MA, Frame AA, Hamburg NM, Vita JA. Relation of mitochondrial oxygen consumption in peripheral blood mononuclear cells to vascular function in type 2 diabetes mellitus. Vasc Med 2014; 19(1): 64-74. 4. VEVERA J, FISAR Z, NEKOVAROVA T, VRABLIK M, ZLATOHLAVEK L, HROUDOVA J, Et al. Statin-Induced Changes in Mitochondrial Respiration in Blood Platelets in Rats and Human With Dyslipidemia. PHYSIOLOGICAL RESEARCH. 2016;65:777-88. 5. Muntean DM, Thompson PD, Catapano AL, Stasiolek M, Fabis J, Muntner P, et al. Statin-associated myopathy and the quest for biomarkers: can we effectively predict statin-associated muscle symptoms? Drug discovery today. 2017 Jan;22(1):85-96.

MitoEAGLE Inclusiveness Target Countries - Conference Grant

• • • • Conference Grant Grand Period 3

Scientific report - MiP2018

Participated at

• MitoEAGLE 2019 Belgrade RS
• MitoEAGLE 2018 Jurmala LV
• MitoEAGLE 2018 Lund SE