Emerging Role of the Mitochondrial Outer Membrane Translocator Protein (TSPO) in Heart Failure and Mitochondrai Quality Control

Abstract

Introduction: Mitochondrial dysfunction is a hallmark of heart failure (HF), resulting in decreased energy production and impaired mitochondrial quality control (mitophagy) with resultant contractile dysfunction and cell death. The 18-kDa mitochondrial translocator protein (TSPO) has been considered a part of the mitochondrial permeability transition pore (mPTP) for a long time; however, its role in mPTP regulation is now debatable and the precise role of the TSPO in cardiac physiology and HF remains poorly understood.Objective: Determine the role of TSPO in a murine pressure-overload model of HF.Methods and Results: Conditional, cardiac-specific TSPO knockout (KO) mice were generated using the Cre-loxP system. Pressure overload by transverse aortic constriction (TAC) for 8 weeks significantly increased TSPO expression in wild type (WT) mice, but not in KO mice. While WT TAC mice showed a marked reduction in systolic function, KO TAC mice did not have a significant reduction in ejection fraction, and also exhibited fewer clinical HF signs (less cardiac dilation and fibrosis). TAC reduced mitochondrial calcium uptake and enhanced mPTP opening in permeabilized myocytes from WT animals. Calcium uptake was restored in TAC KO mice without significant effect on mPTP activity. The restoration of the mitochondrial calcium uptake coincided with reduced oxidative stress, improved oxygen consumption rate, and enhanced ATP generation and mitochondrial reserve capacity. In WT TAC, elevated mitochondrial accumulation of mCherry-Parkin1 was not coupled to the increase in LC3-autophagosomes formation indicating impaired mitophagy. In contrast, mitophagy was normalized in TSPO KO.Conclusions: These data suggest a novel mechanism to prevent HF at the cellular level via normalization of TSPO levels which leads to preservation of mitochondrial calcium uptake, oxidative phosphorylation, and mitochondrial mt-QC resulting in preservation of mitochondrial integrity and cell survival.