Control of Mitochondrial Function by Fusion and Fission

Abstract

Several neurodegenerative diseases are associated with defects in mitochondrial fusion or fission, which are opposing processes that regulate mitochondrial function. This observation raises the issue of whether a defect in one process can be alleviated by simultaneously reducing the opposing process. We used mouse models to address this issue. Mff is a mitochondrial outer membrane protein important for mitochondrial fission. We generated Mff mutant mice and found that they die at 13 weeks due to heart failure caused by dilated cardiomyopathy. Mff cardiac tissue shows reduced mitochondrial density, reduced respiratory chain activity, and increased mitophagy. Mfn1 deficient mice die shortly after birth. However, mice with loss of both Mff and Mfn1 have normal heart function, lifespan and respiratory chain function. The reciprocal rescue with both mutations indicate that retuning mitochondrial dynamics can restore tissue integrity and mitochondrial physiology at the whole organ level.