부산대학교 도서관

Introduction: Defects in ATP production lead to cardiac dysfunction and heart failure (HF) while restoring reduced mitochondrial (Mito) function mitigates HF. Previously we showed that a novel Mito protein, Perm1 (PGC-1 and ERR-induced regulator, muscle 1), promotes Mito biogenesis in cardiomyocytes (CM). Here we studied the role of myocardial Perm1 in vivo.Hypothesis: Perm1 protects the heart from pressure overload-induced dysfunction.Methods: First, we generated cardiac-specific Perm1 transgenic mice (Perm1cTG). Next, we induced pressure overload by transverse aortic constriction (TAC) or performed Sham operations on 10-week-old control (CTL) and Perm1cTG male mice. Heart function, histology, and biochemical analyses were performed eight weeks postoperatively. To understand the mechanism of Perm1, the heart protein samples were subjected to quantitative mass spectrometry (MS) analysis, and we also identified Perm1 binding proteins in the heart by MS. Finally, mouse neonatal CM were infected with adenoviruses expressing shMic60 (knock down) or shControl in combination with Perm1 or LacZ, followed by oxygen consumption rate (OCR) analysis.Results: Sham-operated Perm1cTG and CTL mice showed no differences in function and morphology. Following TAC, CTL developed severely reduced heart function, while Perm1cTG had only minimal change. Perm1cTG TAC mice also showed reduced cardiac hypertrophy, Anf and Bnp mRNA expression, and fibrosis, compared to CTL TAC, showing Perm1 protects the heart from hemodynamic stress. Perm1cTG TAC hearts showed significantly increased OCR compared to CTL TAC, suggesting Perm1 preserves TAC-induced CM Mito dysfunction. MS analysis identified MICOS (mitochondrial contact site and cristae organizing system) and oxidative phosphorylation proteins were upregulated in Perm1cTG TAC hearts compared to CTL TAC. Moreover, we found that Perm1 binds to Mic60, which is a core component of the MICOS. Finally, Mic60 was required for Perm1-induced maximal oxidative capacity, suggesting Perm1 acts through Mic60.Conclusion: Perm1 protects the heart against pressure overload by restoring oxidative metabolism. Future studies will reveal the role of Perm1/Mic60 in the heart. This work is supported by NIH R01HL151239.