Regulation of mitochondrial dynamics and homeostasis by cyclic actin assembly/disassembly

University Of Pennsylvania, Philadelphia PA

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Abstract

Project Summary: Mitochondria form interconnected reticula that dynamically break apart and re-fuse in response to multiple cellular cues. In mammals, mitochondrial fission and fusion are executed by large dynamin-like GTPases, including Opa1, Mitofusins 1 and 2, and Drp1. Mutations in the core fission/fusion machinery have been linked to several human disorders, including Dominant Optic Atrophy, Charcot-Marie-Tooth disease, and lethal encephalopathy. Though numerous investigations have examined the structure and function of the mitochondrial fission/fusion machinery, considerably less is known about the upstream cellular cues that specify mitochondrial dynamics at steady-state. Our recent work demonstrated that the actin cytoskeleton is a key regulator of mitochondrial network morphology. Specifically, we observed that F-actin assembles on locally hyperfused mitochondria where it inhibits fusion and promotes robust Drp1-dependent fission. Upon actin depolymerization, mitochondria quickly re-fuse, forming new connections and reintegrating into the larger network. Over time, actin transiently assembles on all mitochondrial subpopulations in a sequential, step-wise cycle. Here, I propose to investigate the precise mechanism of actin assembly on to and disassembly off of mitochondria. Next, I will investigate the process of mitochondrial actin-cycling during different stages of the cell cycle. Finally, I will elucidate the role of CDK1 in regulating actin cycling. The work proposed here will provide mechanistic insights into the steady-state regulation of mitochondria networks by the actin cytoskeleton.