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

Research output: Contribution to journalArticle

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 Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct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

Details

Authors
Organisations
External organisations
  • Victor Babes University of Medicine and Pharmacy
  • Abliva AB
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Pharmacology and Toxicology

Keywords

  • Cell-permeable succinate, HepG2 cells, Mitochondria, NV118, Platelets, Statins
Original languageEnglish
Article number424
Number of pages15
JournalInternational Journal of Molecular Sciences
Volume22
Issue number1
Publication statusPublished - 2021
Publication categoryResearch
Peer-reviewedYes