Avram 2021 Int J Mol Sci
|Avram VF, Chamkha I, Åsander-Frostner E, Ehinger JK, Timar RZ, Hansson MJ, Muntean DM, Elmér E (2021) Cell-permeable succinate rescues mitochondrial respiration in cellular models of statin toxicity. Int J Mol Sci 22:424.|
Abstract: Statins are the cornerstone of lipid-lowering therapy. Although generally well tolerated, statin-associated muscle symptoms (SAMS) represent the main reason for treatment discontinuation. Mitochondrial dysfunction of complex I has been implicated in the pathophysiology of SAMS. The present study proposed to assess the concentration-dependent ex vivo effects of three statins on mitochondrial respiration in viable human platelets and to investigate whether a cell-permeable prodrug of succinate (complex II substrate) can compensate for statin-induced mitochondrial dysfunction. Mitochondrial respiration was assessed by high-resolution respirometry in human platelets, acutely exposed to statins in the presence/absence of the prodrug NV118. Statins concentration-dependently inhibited mitochondrial respiration in both intact and permeabilized cells. Further, statins caused an increase in non-ATP generating oxygen consumption (uncoupling), severely limiting the OXPHOS coupling efficiency, a measure of the ATP generating capacity. Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct complex I inhibition. NV118 increased succinate-supported mitochondrial oxygen consumption in atorvastatin/cerivastatin-exposed platelets leading to normalization of coupled (ATP generating) respiration. The results acquired in isolated human platelets were validated in a limited set of experiments using atorvastatin in HepG2 cells, reinforcing the generalizability of the findings.
Labels: MiParea: Respiration, Pharmacology;toxicology
Organism: Human Tissue;cell: Platelet Preparation: Intact cells
Coupling state: LEAK, ROUTINE, ET Pathway: ROX HRR: Oxygraph-2k
2021-01, MitoKit-CII, RO, SE