Mitochondrial Translocator Protein (TSPO) Prevents Heart Failure by Increasing Cardiac Utilization of Fatty Acids

Abstract

Introduction: For more than two decades, the peripheral mitochondrial translocator protein (TSPO) was considered to play a major role in mPTP formation, cholesterol transport, and steroidogenesis. However, recent genetic studies have questioned these previously established functions of TSPO, and therefore, the exact molecular mechanism of TSPO action remains unclear. We have previously demonstrated that TSPO expression was significantly upregulated in heart failure (HF) induced by transverse aortic constriction (TAC) in mice, and cardiac-specific conditional knockout (KO) of TSPO limited the development of pressure overload induced HF (Thai, Sci Reports, 2018, 8(1):16213). However, the exact mechanism of this protection has not been elucidated. Objective: Determine the mechanism of TSPO KO protection against pressure-overload HF. Methods and Results: We examined protein profiles in hearts from 4 experimental groups (WT sham, KO sham, WT TAC and KO TAC) using liquid chromatography-mass spectrophotometry. Our data revealed major changes in NADH:ubiquinone oxidoreductase subunit AB1 of the mitochondrial complex I (NDUFAB1), mitochondrial acyl-CoA binding protein (ACBP), mitochondrial long-chain specific acyl-CoA dehydrogenase (ACADL), and mitochondrial D-2-hydroxyglutarate dehydrogenase between KO and WT animals, with more modest changes in cytoskeletal and collagen associated proteins. Since NDUFAB1 and ACBP participate in free fatty acids (FFA) synthesis and ACADL is an important enzyme in FFA oxidation (FAO) pathway, we tested whether TSPO modulates FFA biosynthesis and oxidation.We measured changes in FAO in WT and TSPO KO mice under sham and TAC conditions and found that TSPO KO significantly increased fatty acid consumption and oxidation. Conclusion: Since HF is characterized by a shift in metabolism from FFA to less efficient glycolysis, thereby resulting in energetic failure, contractile dysfunction and cell death, the recovery of FFA metabolism by TSPO inhibition may be an effective drug target for HF.