Defining molecular interactions that drive mitochondrial fission

Case Western Reserve University, Cleveland OH

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Abstract

ABSTRACT Mitochondria fission and fusion are dynamic processes that must be regulated to maintain cell health. Excessive or reduced fission can result in an imbalance of ATP, and neurons and synapses can suffer reduced functionality or even degeneration if these appropriate ATP levels are not maintained. Dynamin- related protein 1 (Drp1) regulates mitochondria fission; however, the mechanism of action and the native structure of cytosolic Drp1 is unknown. The goal of this supplement is to complement the structural studies of Drp1 detailed in the parent grant by expanding the scope and to expand the research into a prospective study on mitochondria morphology in the white matter of human multiple sclerosis (MS) tissue samples. This will be accomplished through two specific aims. First, the native structure of the Drp1 in solution will be determined using cryo-EM. By resolving the first cytosolic, atomic structure of the Drp1 dimer alone and in the presence of partner proteins, the molecular mechanism of mitochondria fission can be studied and potential therapeutic targets can be identified. Second, mitochondria morphology changes will be identified in neurodegenerative models. By studying contact sites between mitochondria and smooth endoplasmic reticulum, changes in cellular mitochondria fission will be characterized. Quantifying these changes in disease tissue compared to normal tissue will determine the role fission plays in neurodegeneration.