Abstract 11298: Bioenergetics-Independent Stress Response to Mitochondrial Protein Import Clogging in the Heart

Mitochondria are double-membraned organelles indispensable in metabolically active organs such as the heart. Much of the mitochondrial proteome is encoded by the nuclear genome and requires import into mitochondria via channels present on the outer and inner mitochondrial membranes. If protein import goes awry at any step, it can cause unimported mitochondrial proteins to accumulate in the cytosol, leading to mitochondrial Precursor Overaccumulation Stress (mPOS). Defects in mitochondrial protein import have been linked to many forms of heart disease such as Senger’s syndrome, cardiac arrhythmia, and chronic atrial fibrillation. The A123D mutation in adenine nucleotide translocase 1 (Ant1), an ATP/ADP antiporter present on the mitochondrial inner membrane, has been shown to cause hypertrophic cardiomyopathy, while other mutations in Ant1 (A114P, A90D, V289M, L98P) have been shown to cause Autosomal Dominant Progressive External Ophthalmoplegia. Our studies suggested that the mutant ANT1 can cause mitochondrial protein import clogging. To characterize the pathophysiology induced by mitochondrial protein import clogging, we developed a mouse model (the “clogger mouse”) expressing two clinically relevant mutations in Ant1 , namely A114P and A123D . While prior work on this model revealed a low-penetrant neurodegenerative and mild myopathic phenotype, the impact of this mutation on the heart has not been studied. In the current study, we show that expression of Ant1 A114P, A123D has little effect on mitochondrial respiration and heart function. This is consistent with the rapid degradation of Ant1 A114P, A123D in the heart. Interestingly, transcriptomic analysis revealed an altered expression of circadian regulator and output genes such as Clock, Ciart, Per1-3, Cebpb and Hlf in the clogger mouse relative to wild type. These data suggest that mitochondrial protein import clogging can induce a stress response independent of bioenergetics. It also led us to hypothesize that the circadian pathway plays a role in adapting to mitochondria-induced proteostatic stress in the heart. Our current experiments focused on testing this hypothesis are anticipated to help us understand how the heart can uniquely adapt to mitochondrial protein import clogging.