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

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 Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct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

Mitochondrial Dysfunction in Vascular Wall Cells and Its Role in Atherosclerosis

“…It is therefore important to develop treatments that will allow alleviating the toxic side effects of statins on the mitochondria. Recently, cell-permeable succinate was shown to restore mitochondrial respiration in experimental cellular models of statin toxicity [95]. These promising results may lead to improvement of statin therapy in the future.…”

Cell-Permeable Succinate Increases Mitochondrial Membrane Potential and Glycolysis in Leigh Syndrome Patient Fibroblasts

“…Presently, there is very little evidence of targeted therapies for LS [ 4 , 5 ]. Recent studies has highlighted the potential for cell-permeant substrates regulating the electron transport chain (ETC) as therapeutics for mitochondrial diseases [ 6 , 7 , 8 , 9 , 10 , 11 ]. These substrates work by increasing tricarboxylic acid cycle (TCA) intermediates and providing alternative substrate sources for energy production in the mitochondria.…”

“…These substrates work by increasing tricarboxylic acid cycle (TCA) intermediates and providing alternative substrate sources for energy production in the mitochondria. One of the mitochondrial substrates that is currently being explored as a therapeutic option for LS is succinate [ 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. Conversion of succinyl-CoA by the enzyme succinyl-CoA synthetase yields free succinate as an intermediate substrate of the TCA cycle, to form GTP which further donates its terminal phosphate group to ADP to form ATP [ 14 ].…”

“…NV101-118 (NV118, diacetoxymethyl succinate), hereafter referred to as NV118, is one of the successful cell membrane-permeable prodrugs of succinate that was recently developed [ 9 ]. Since its development, NV118 has been explored as a potential therapeutic for various diseases [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 20 ]. NV118 is currently being tested for its therapeutic potential in various cellular models of diseases associated with CI dysfunction [ 7 , 8 , 9 , 10 , 11 , 20 ].…”

“…Since its development, NV118 has been explored as a potential therapeutic for various diseases [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 20 ]. NV118 is currently being tested for its therapeutic potential in various cellular models of diseases associated with CI dysfunction [ 7 , 8 , 9 , 10 , 11 , 20 ]. In all of these models, NV118 improved mitochondrial function, as evidenced by increased CII-linked respiration, membrane potential, ATP production, and a decrease in lactic acidosis [ 9 , 11 , 20 ].…”