Energy metabolic reprogramming occurs in the developing and diseased hearts. Mitochondria are responsible for coordinating cellular energy production in response to physiological and pathological stimuli. The mitochondrial regulatory system is highly regulated by several transcription factors and coactivators that orchestrate the expression of genes involved in mitochondrial biogenesis, maintenance, and respiration capacity. However, the transcriptional regulatory machinery in mitochondrial bioenergetics is complex, and it is still not completely understood how mitochondria coordinately respond to physiological and pathological stimuli. Perm1 (?PGC-1 and ERR regulator in muscle 1?) was recently identified in skeletal muscle, as a novel muscle-specific protein that regulates mitochondrial oxidative capacity. Perm1 is induced by exercise, and the increased expression of Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in mouse skeletal muscle. These findings point to a new path towards understanding mitochondrial myopathies and muscle atrophies. However, the role of Perm1 in the heart has never been investigated. Moreover, the regulatory mechanism of Perm1 in mitochondrial function is currently unknown. Our preliminary data suggest the significant role of Perm1 in cardiac pathophysiology: (1) Perm1 is highly expressed in the heart and is downregulated in the mouse failing heart and in patients with heart failure; (2) Perm1 expression is increased during differentiation and maturation in human iPS cell-derived cardiomyocytes; (3) Perm1 knockdown in cultured cardiomyocytes leads to reduced mitochondrial respiration capacity. Furthermore, our preliminary data suggest that Perm1 controls mitochondrial function through the regulation of ERR?, a well-known transcription factor that orchestrates the expression of genes in mitochondrial bioenergetics. This application will leverage a genetic animal model and state-of-the art multisystems approach to conceptually advance our understanding of mitochondrial bioenergetics in the heart. Specifically, this work is expected to demonstrate that Perm1 is a critical regulator of mitochondrial biosynthesis and energetics in the heart through the ERR? pathway. Furthermore, this study will determine if gene delivery of Perm1 to the heart protects against mitochondrial impairment and cardiac dysfunction in the setting of pressure-overload-induced heart failure. Conclusive evidence that Perm1 is a novel transcriptional cofactor of the mitochondrial regulatory pathway in the heart will profoundly advance our knowledge of cardiac metabolism, and may suggest new therapeutic approaches for heart failure.
The heart constantly requires energy to work. Mitochondria, which are renowned as being ?the powerhouse of the cell?, supply continuous energy to the cardiac cells. Mitochondria malfunction is closely linked to development defects and dysfunction in the heart. This application seeks to advance our understanding of metabolic reprogramming of the heart through mitochondrial signaling pathways during postnatal development and pathological development. Specifically, this proposal will utilize a genetic model and state-of-the-art multisystems approach to determine the role of the novel muscle-specific mitochondrial regulator Perm1 in mitochondrial biogenesis and energetics in the healthy and diseased hearts.
