Regulation of Mitochondrial Dynamics during Apoptosis and the Cell Cycle

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2010

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Abstract

Homeostatic maintenance of cellular mitochondria requires a dynamic balance between fission and fusion, and disruptions in this balance have been implicated in multiple pathological conditions, including Charcot-Marie-Tooth, Parkinson's, and Alzheimer's diseases. Whereas deregulated fission and fusion can be detrimental to health and survival, controlled changes in morphology are important for processes like cellular division and apoptosis. Specifically, regulated mitochondrial fission occurs closely with cytochrome c release during apoptosis and upon entry into mitosis during the cell cycle. Using cell culture-based assays, microscopy, and fly genetics, we examine how changes in the mitochondrial network are mediated at the molecular level during apoptosis and the cell cycle.

First, we report that the fly protein Reaper induces mitochondrial fragmentation in mammalian cells, likely through inhibition of the mitochondrial fusion protein Mfn2. Reaper colocalizes with and binds to Mfn2 and its fly orthologue dMFN, and the colocalization of the two proteins is necessary for Reaper-induced mitochondrial fission. Moreover, the overexpression of dMFN inhibits Reaper-induced killing both in vitro and in vivo.

Our data and work in a number of experimental systems demonstrate a requirement for mitochondrial fragmentation during apoptosis that is conserved from worms to flies to mammals. Our findings indicate that Reaper may function to inactivate mitochondrial metabolic function and/or to facilitate mitochondrial elimination during apoptosis.

Secondly, we characterize Drp1 degradation by the APC/C during mitotic exit and interphase. We provide evidence that APC/CCdh1-mediated degradation of Drp1 underlies both the morphological changes that occur during progression through the cell cycle and changes in mitochondrial metabolism during interphase. Inhibition of Cdh1-mediated Drp1 ubiquitylation and proteasomal degradation during interphase prevents the normal regrowth of mitochondrial networks after mitosis, prevents cyclin E accumulation, and alters the profile of lipid-derived metabolites. Our findings describe a novel role for APC/CCdh1-mediated Drp1 degradation in cell cycle-dependent changes in mitochondrial morphology and metabolic function and suggest that the APC/CCdh1complex may regulate the distinct bioenergetic needs of a growing cell during synthetic phases of the cell cycle.

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Horn, Sarah R. (2010). Regulation of Mitochondrial Dynamics during Apoptosis and the Cell Cycle. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/2281.

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