Avram 2018 MiP2018

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MiPsociety
Cell-permeable succinate bypasses statin-induced mitochondrial complex I inhibition in human platelets. Avram_Presentation

Link: MiP2018

Avram VF, Asander Frostner E, Hansson M, Muntean DM, Elmer E (2018)

Event: MiP2018

COST Action MitoEAGLE

Statins are pleiotropic drugs currently recognized as the cornerstone of prevention and treatment in cardio-metabolic diseases that have been reported to elicit several side-effects among which mitochondrial dysfunction plays a central role [1]. Recently, a decrease in complex I-supported respiration has been reported in permeabilized (but not intact) platelets harvested from patients after short-term treatment with statins [2]. Cell-permeable succinate prodrugs have been successfully used previously to bypass mitochondrial complex I deficiency of different etiology [3,4]. The present study was purported to assess the effects of two statins on mitochondrial respiration in intact and permeabilized human platelets in the presence vs. the absence of NV118, a cell-permeable succinate prodrug.

To this aim peripheral blood platelets were isolated from healthy volunteers by differential centrifugations (using K-EDTA as anticoagulant). Respiratory capacities of intact and permeabilized cells (200 x 106 cells/mL) were analyzed using the substrate-uncoupler-inhibitor titration protocols following acute incubation with increasing doses of cerivastatin and atorvastatin in the presence vs. the absence of the cell-permeable complex II substrate, NV118. Digitonin was used for platelet permeabilization and sequential addition of complex-specific respiratory substrates and inhibitors was performed using the MiR05 buffer.

In both intact and permeabilized cells, cerivastatin demonstrated a dose-dependent (20-160 μm) respiratory inhibition. A comparable deleterious effect on mitochondrial respiration was observed for atorvastatin (80 μm) in each experimental condition. The addition of the cell-permeable succinate prodrug to intact platelets exposed to cerivastatin or atorvastatin increased mitochondrial respiration above the routine level. Representative traces of the beneficial effects of NV118 in statin-treated intact platelets are shown in Fig 1.

The cell-permeable succinate prodrug alleviated the respiratory deficit and bypassed the mitochondrial dysfunction induced by statins. Whether this effect can be recapitulated in platelets isolated from patients chronically treated with statins certainly warrants further investigation.


Bioblast editor: Plangger M, Kandolf G O2k-Network Lab: RO Timisoara Muntean DM, SE Lund Elmer E


Labels: MiParea: Respiration, Pharmacology;toxicology 


Organism: Human  Tissue;cell: Platelet  Preparation: Intact cells, Permeabilized cells 


Coupling state: LEAK, ET  Pathway:HRR: Oxygraph-2k 


Affiliations

Avram VF(1), Åsander Frostner E(2,3), Hansson M(2,3), Muntean DM(1+), Elmér E(2,3,4)

  1. Dept Pathophysiology-Functional Sciences, +Centre Translational Research Systems Medicine, "Victor Babeș" Univ Medicine Pharmacy, Timișoara, Romania
  2. Dept Clinical Sciences, Mitochondrial Medicine, Lund Univ
  3. NeuroVive Pharmaceutical AB, Medicon Village
  4. Skane Univ Hospital, Clinical Neurophysiology; Lund, Sweden

Figures

Avram Figure MiP2018.jpg
Figure 1. Oxygen consumption of intact platelets in the presence of cerivastatin (upper panel) and atorvastatin (lower panel): the effect of succinate prodrug (NV118) vs.control (DMSO).














References

  1. Muntean DM, Thompson PD, Catapano AL, Stasiolek M, Fabis J, Muntner P, Serban MC, Banach M (2017) Statin-associated myopathy and the quest for biomarkers: can we effectively predict statin-associated muscle symptoms? Drug Discov Today 22:85–96.
  2. Vevera J, Fišar Z, Nekovářová T, Vrablík M, Zlatohlávek L, Hroudová J, Singh N, Raboch J, Valeš K (2016) Statin-induced changes in mitochondrial respiration in blood platelets in rats and humans with dyslipidemia. Physiol Res 65:777-788
  3. Piel S, Ehinger JK, Elmer E, Hansson MJ (2013) Metformin induces lactate production in peripheral blood mononuclear cells and platelets through specific mitochondrial complex I inhibition. Acta Physiol (Oxf) 213:171-80.
  4. Ehinger JK, Piel S, Ford R, Karlsson M, Sjövall F, Åsander Frostner E, Morota S,Taylor RW, Turnbull DM, Cornell C, Moss SJ, Metzsch C, Hansson MJ, Fliri H, Elmer E (2016) Cell-permeable succinate prodrugs bypass mitochondrial complex I deficiency. Nat Commun 7:12317.