Improvement of Platelet Respiration by Cell–Permeable Succinate in Diabetic Patients Treated with Statins

Abstract

Diabetes mellitus (DM) is the most severe metabolic disease that reached the level of a global pandemic and is associated with high cardiovascular morbidity. Statins are the first–line lipid–lowering therapy in diabetic patients with or without a history of atherosclerotic disease. Although well tolerated, chronic treatment may result in side effects that lead to treatment interruption. Mitochondrial dysfunction has emerged as a central pathomechanism in DM– and statin–induced side effects. Assessment of mitochondrial respiration in peripheral platelets has been increasingly used as a mirror of organ mitochondrial dysfunction. The present study aimed to assess the: (i) changes in mitochondrial respiration elicited by statins in patients with type 2 DM and (ii) the effects of cell–permeable succinate (NV118) on respiratory parameters in platelets harvested from these patients. No significant changes were found in global mitochondrial respiration of intact platelets isolated from diabetic patients treated with either atorvastatin or rosuvastatin. Similarly, no significant changes in mitochondrial respiration of permeabilized platelets were found between diabetic patients treated with atorvastatin and healthy controls. Acute ex vivo administration of NV118 significantly improved respiration in isolated platelets. These results prompt further research on the role of permeable succinate as a therapeutic alternative for improving mitochondrial function in metabolic pathologies and point to the role of peripheral platelets as a potential biomarker of treatment response.

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

“…Respiratory parameters-definitions and calculation (as previously presented in [ 20 , 57 ]): ROUTINE respiration: mitochondrial oxygen consumption in the physiological coupling state; LEAK respiration (non-phosphorylating respiration): mitochondrial oxygen consumption after inhibition of ATP-synthase; ET capacity: mitochondrial oxygen consumption in a fully uncoupled state achieved by the titration of optimum concentration of FCCP (protonophore); NADH-linked OXPHOS capacity: mitochondrial oxygen consumption at saturating concentrations of ADP and complex I substrates; OXPHOS capacity (phosphorylating respiration): mitochondrial oxygen consumption at saturating concentrations of ADP with both complex I and complex II substrates; Residual succinate-supported respiration: mitochondrial oxygen consumption after inhibition of complex I using rotenone; P-L control efficiency: calculated by subtracting LEAK respiration from OXPHOS capacity and then dividing the result by the OXPHOS capacity, it is a measure of the state of coupling (ATP generation) of the ETS; E-L coupling efficiency: calculated by subtracting LEAK respiration from ET capacity and then dividing the result by the ET capacity, as a measure of the degree of coupling (ATP generation). …”

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 ].…”