Mitoguardin Regulate Mitochondrial Fusion Through MitoPLD And Required For Neuronal Homeostasis

Mitochondrial is a highly dynamic organelle, it undergoes frequent fusion and fission and is crucial for cell metabolism. Core members of the fusion or fission machinery would lead to severe neurodegenerative diseases. Currently, the mitochondrial outer membrane fusion model is described as follows:MFN proteins tether the mitochondria together and pull the mitochondria that are in close proximity while MitoPLD catalyzes phosphatidic acid (PA) formation to change membrane properties and mediate fusion. Surprisingly, recent structural studies challenge that MitoPLD has a PLD activity. The structure of MitoPLD reveals a greater architectural similarity to phospholipase D family nucleases than to phospholipase, suggesting that MitoPLD may catalyze PA formation with the help of additional proteins. In our study, we uncovered an evolutionarily conserved new family of proteins:MIGA. We found MIGA proteins are outer membrane mitochondrial proteins required for mitochondrial fusion. We proposed a model in which MIGA functions downstream of MFN and interacts with MitoPLD, a protein that promotes mitochondrial fusion by regulating phosphatidic acid (PA) formation on the mitochondrial surface. Miga can stabilize MitoPLD and regulate its self-association affinity, results in accumulation of PA on the mitochondria, and mediates mitochondrial fusion. Therefore, our study not only provides a missing link for the current mitochondrial OM fusion model but also present a new angle to our understanding of neurodegeneration and fat metabolism.In summary, We proposed that Mitoguardin, a novel mitochondrial protein, regulates mitochondrial fusion through MitoPLD and is required for neuronal homeostasis.