Altered division, or fission, of mitochondria has severe consequences even death. Yet the reasons for this are unknown. It is postulated that the mitochondria have their own lifecycle that involves fission of unhealthy mitochondria to remove them in an autophagic process called mitophagy. These quality control processes are evolutionarily conserved between budding yeast and humans, although extent to which has recently been called into question. In yeast, fission requires the protein FIS1 that is now thought to be dispensable for fission in mammals, but indispensable for mitophagy. Consistent with this view are FIS1 interactions in mitophagy human cell culture. Contrary to this view, loss of FIS1 elongates mitochondrial and displaces the fission mechanoenzyme DRP1 from mitochondria in some, but not all, cell types. Mutations to some evolutionarily conserved residues in FIS1 impair fission and DRP1 localization. Mutations to different conserved residues impair binding to a critical adaptor in mitophagy, the Rab7 GTPase Activating Proteins TBC1D15 and TBC1D17. These findings suggest that FIS1 is conserved for roles in both fission and mitophagy. Using yeast- inspired mutations, along with state-of-the-art genetic, microscopic, and structural tools, we are now poised to determine how conserved components govern the fate of mitochondria between fission, mitophagy, or apoptosis. To understand the protein-protein interactions that govern this, biochemical and structural studies will be integrated with state-of-the-art cell biological and genetic approaches. A better understanding of the protein machinery and how it works will identify key points of regulation that may be targeted in future studies with small molecules to inhibitor, and activate fission, mitophagy, and apoptosis. The discovery of such molecules may ultimately lead to treatments for diseases in which enhanced, or impaired, fission activity is central.
Mitochondria are components of cells that perform many functions critical for life and are known for being the 'power plant' of the cells. The mitochondria have their own life cycle with a mechanism to destroy damaged mitochondria that involves a splitting event that separates a healthy daughter mitochondrion from an unhealthy one that is subsequently removed by the cell. The work proposed will illuminate mechanistic details of these processes and represents an important step towards the discovery of new therapeutic strategies for both rare and common human diseases, including cardiac and neurodegenerative diseases, cancer, diabetes, aging, and neonatal lethality syndrome.
|Ma, Cui; Beyer, Andreas M; Durand, Matthew et al. (2018) Hyperoxia Causes Mitochondrial Fragmentation in Pulmonary Endothelial Cells by Increasing Expression of Pro-Fission Proteins. Arterioscler Thromb Vasc Biol 38:622-635|
|Egner, John M; Jensen, Davin R; Olp, Michael D et al. (2018) Development and Validation of 2D Difference Intensity Analysis for Chemical Library Screening by Protein-Detected NMR Spectroscopy. Chembiochem 19:448-458|
|Santarriaga, Stephanie; Haver, Holly N; Kanack, Adam J et al. (2018) SRCP1 Conveys Resistance to Polyglutamine Aggregation. Mol Cell 71:216-228.e7|
|Harwig, Megan C; Viana, Matheus P; Egner, John M et al. (2018) Methods for imaging mammalian mitochondrial morphology: A prospective on MitoGraph. Anal Biochem 552:81-99|
|Widlansky, Michael E; Hill, R Blake (2018) Mitochondrial regulation of diabetic vascular disease: an emerging opportunity. Transl Res 202:83-98|
|Bordt, Evan A; Clerc, Pascaline; Roelofs, Brian A et al. (2017) The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor that Modulates Reactive Oxygen Species. Dev Cell 40:583-594.e6|
|Bakkum, Amber L; Hill, R Blake (2017) Removal of a consensus proline is not sufficient to allow tetratricopeptide repeat oligomerization. Protein Sci 26:1974-1983|
|Lee, Michelle W; Lee, Ernest Y; Lai, Ghee Hwee et al. (2017) Molecular Motor Dnm1 Synergistically Induces Membrane Curvature To Facilitate Mitochondrial Fission. ACS Cent Sci 3:1156-1167|
|Koppenol-Raab, Marijke; Harwig, Megan Cleland; Posey, Ammon E et al. (2016) A Targeted Mutation Identified through pKa Measurements Indicates a Postrecruitment Role for Fis1 in Yeast Mitochondrial Fission. J Biol Chem 291:20329-44|
|Cahill, Thomas J; Leo, Vincenzo; Kelly, Matthew et al. (2016) Resistance of dynamin-related protein 1 oligomers to disassembly impairs mitophagy, resulting in myocardial inflammation and heart failure. J Biol Chem 291:25762|
Showing the most recent 10 out of 26 publications