Regulated Mitochondrial Morphology The mitochondrial reticulum performs an astonishing number of essential cellular functions, including respiratory energy production, anabolic production of critical metabolites, and regulated cell death. Mutations, injuries, and infections degrade mitochondrial activity; and damaged or dysfunctional mitochondria are increasingly recognized as contributing if not causative factors for a long and still growing list of diseases. The most commonly observed defect seen in aging, injured, or diseased cells is a breakdown of the inter-connected reticulum into hyper-fragmented organelle units that lose their chemical potential and the integrity of their genomes. The observation of hyper-fission in disease settings generated clinical interest in specific inhibitors of the mitochondrial fission machinery to ameliorate a range of illness: from chronic neurodegeneration and certain cancers to more acute injuries like heart attack and stroke?with promising proof-of-concept studies in animal models. Progress has been slow, however, in part because we do not understand the molecular mechanisms that govern mitochondrial fission. Recent biochemical breakthroughs in our lab?in combination with the resolution revolution in electron cryo-microscopy or cryoEM?have finally prepared us to resolve the mechanisms that drive these fission machines in unprecedented detail. We propose to determine the structural mechanisms that govern recruitment and assembly of the fission machine on the surface of mitochondria through the activity of specialized receptors (Aim1). We further propose to determine the allosteric protein motions that harness the chemical energy present in guanine nucleotides to perform mechanical, constricting work on mitochondrial tubules (Aim 2). Finally, we propose to determine how post-translational modifications?including phosphorylation and SUMOylation?tune or turn off the activity of the fission machinery (Aim 3). Together, accomplishing these objectives will provide new and unique insights into how these fundamental cellular machines work and will enable a new generation of structure-guided studies to identify and characterize novel therapeutic opportunities.

Public Health Relevance

The mitochondrial reticulum is an essential but still poorly understood organelle. Perturbations of mitochondrial morphology underlie certain human diseases, and our lab has recently discovered new molecular mechanisms that are responsible for the fragmentation of the mitochondrial reticulum. This project will advance our understanding of how cells regulate mitochondrial morphology in response to injury, infection and other stressors.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM127673-03
Application #
10004687
Study Section
Membrane Biology and Protein Processing Study Section (MBPP)
Program Officer
Flicker, Paula F
Project Start
2018-09-19
Project End
2022-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Biochemistry
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118