Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Statin Toxicity

Vlad F. Avram, Imen Chamkha, Eleonor Åsander-Frostner, Johannes K. Ehinger, Romulus Z. Timar, Magnus J. Hansson, Danina M. Muntean, Eskil Elmér

Research output: Contribution to journalArticlepeer-review

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 mito-chondrial 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 Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct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.

Original languageEnglish
Article number424
Number of pages15
JournalInternational Journal of Molecular Sciences
Volume22
Issue number1
DOIs
Publication statusPublished - 2021

Subject classification (UKÄ)

  • Pharmacology and Toxicology

Keywords

  • Cell-permeable succinate
  • HepG2 cells
  • Mitochondria
  • NV118
  • Platelets
  • Statins

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