Date of Award
Doctor of Philosophy (PhD)
Mitochondrial health is essential to heart function. Unlike fibroblasts and many other type of cells that constantly undergo mitochondrial fission and fusion, adult cardiomyocyte mitochondria are hypo-dynamic. Yet, mitochondrial dynamism proteins are abundantly expressed in the adult heart and how cardiac mitochondrial fission and fusion relate to organelle quality control is unclear. Here, we performed parallel studies in cultured murine embryonic fibroblasts (MEFs) and in vivo mouse hearts to uncover distinct effects on mitophagy of acutely inhibiting Drp1-mediated mitochondrial fission versus mitofusin-mediated mitochondrial fusion. Our results showed that Drp1 ablation evoked dilated cardiomyopathy with mitochondrial enlargement, increased MPTP-mediated cell death, and loss of mitochondria due to increased Parkin-mediated mitophagy. Mfn1/Mfn2 deletion provoked eccentric remodeling with mitochondrial fragmentation and accumulation of defective mitochondria due to suppressed Parkin-mediated mitophagy. Taken together, we discovered that inhibiting mitochondrial fission and fusion had opposing effects on mitophagy, cell viability, and cardiac remodeling, and thus unraveled their non-canonical roles during in vivo cardiac mitochondrial quality control in an integrated homeostatic pathway.
Given the importance of mitochondrial fission and fusion in maintaining mitochondrial health to properly fuel cardiac contraction, it is intriguing that no genetic mutations in mitochondrial dynamism factors have been discovered to cause human cardiac diseases. Here, we performed Mfn2 gene sequencing in a cohort of 286 patients with unexplained cardiac hypertrophy and found 6 nonsynonymous mutations. By bioinformatics prediction and statistical analysis, we identified R400Q as the most damaging variant. Functional studies in multiple experimental systems showed that human Mfn2-Q400 interrupted tethering-mediated sarcoplasmic reticular-mitochondrial calcium signaling and caused ventricular concentric hypertrophy with normal cardiac contractility, which recapitulated the patient phenotype. These findings demonstrated the pathological potential of Mfn2-Q400, linking Mfn2 mutations to a novel category of mitochondrial cardiomyopathy.
Chair and Committee
Gerald W Dorn II
Jeanne Nerbonne, Aaron DiAntonio, Richard Kitsis, Daniel Ory, Jianyi Zhang, Scot Matkovich
Song, Moshi, "Mitochondrial Dynamism and Mitochondrial Quality Control in the Heart" (2015). Arts & Sciences Electronic Theses and Dissertations. 683.
Available for download on Sunday, December 15, 2115