Mitofusin Activation Delays Aging in Caenorhabditis elegans

Age-linked tissue dysfunction is associated with mitochondrial degeneration manifested as organelle fragmentation and respiratory dysfunction. Efforts to mitigate downstream consequences of mitochondrial degeneration, as with ROS scavengers, have not translated to the human condition. We posit that intrinsic fusion-mediated mechanisms for mitochondrial protection modulate aspects of aging linked to mitochondrial abnormalities. In C. elegans roundworms mitochondrial fusion is mediated by the mitofusin ortholog Fuzzy Onion-1 (fzo-1). Here, the addition of a mitofusin inhibitor, MFI8, to cultures of age-synchronized C. elegans shortened worm lifespan in a concentration-dependent manner. Reciprocally, the mitofusin activators Chimera and 8015-P2 prolonged worm survival in a dose-dependent manner. The pro-survival effect of Chimera was absent in worms lacking its protein target, FZO-1, and at lower concentrations Chimera-amplified survival was further increased by absence of the mitochondrial fission protein that acts in opposition to fzo-1, DRP-1. The mitofusin activator 8015-P2, which is more potent than Chimera, exhibited greater anti-aging effects on lifespan and improved worm healthspan measured as forced swimming activity and resistance to thermal and oxidative stresses. These proof-of-concept worm studies identify aging phenotypes reciprocally related to fzo-1/mitofusin activation status. As 8015-P2 is under development for use in human neurodegenerative diseases, it might alleviate aging phenotypes evoked by mitochondrial degeneration in higher species.