Abstract 21307: Mitofusin 2 Regulates Cardiac Function Through the Maintenance of Cellular Metabolism
Mitofusin 2 (MFN2) mediates various cellular functions such as mitochondrial fusion, cell proliferation, cell death, juxtaposition between endoplasmic reticulum and mitochondria, and more recently mitochondrial DNA stability. Although expressed abundantly in the heart, the cardiac function of MFN2 remains largely unknown. Here we demonstrate, for the first time, the crucial role of MFN2 in regulating cardiac metabolism and function. Striking abnormalities of subcellular ultrastructure were observed in Mfn2 null heart by Electron microscope assay, including enlarged mitochondria, increased amount of autophagic vacuoles, and accumulation of abnormal multi-membrane endoplasmic reticulum (ER) -like structures. Consistently, ER stress related genes ATF4, CHOP, TRB3, ASNS, Nqo1, and Gsta1/2 were up-regulated from 2 to 35 folds in Mfn2 KO hearts as compared with control hearts. Moreover, LC3BII, the marker of autophagy, significantly increased in Mfn2 knockout mouse hearts, as indicated by 2 fold increased protein level and elevated number of punctate immunofluorescent staining. Preventing the fusion of autophagosome with lysosome by lysosome inhibitor NH4Cl and pepstatin A further increased LC3BII protein level in both untreated and ischemia-reperfusion treated hearts from control mice as expected, surprisingly, it failed to elevate LC3BII level in Mfn2 knockout mouse hearts, indicating the impaired function of autophagosome and lysosome fusion, the end stage of autophagic process, in Mfn2 deficient heart. Cardiac specific Mfn2 knockout mice at age of 4 month old showed about 60∼70% decrease of ATP content in the heart comparing with those of control littermates, and the cardiac contractile activity was decreased significantly at age of 18-month old, accompanied with increased fibrosis and glycogen accumulation. Taken together, our data provide evidence illustrating that deficiency of MFN2 disturbs cardiomyocyte metabolism by inducing ER stress and impairing cellular autophagic process, which eventually leads to decreased cardiac function, suggestive of an important role of MFN2 in regulating cardiac function through the maintenance of normal cellular metabolism.
- © 2010 by American Heart Association, Inc.