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.
The proposed supplement is relevant to public health because it will provide structural understanding of the protein that regulates an important cellular function?mitochondria fission. Excessive or reduced fission has been identified as a causal factor in several human pathologies, including neurodegenerative diseases. Through a prospective study, mitochondria fission dysfunction will be characterized in the context of multiple sclerosis models through a pharmacology and neuroscience collaboration.
|Lu, Bin; Kennedy, Bridget; Clinton, Ryan W et al. (2018) Steric interference from intrinsically disordered regions controls dynamin-related protein 1 self-assembly during mitochondrial fission. Sci Rep 8:10879|
|Tandler, Bernard; Hoppel, Charles L; Mears, Jason A (2018) Morphological Pathways of Mitochondrial Division. Antioxidants (Basel) 7:|