# Regulated Mitochondrial Morphology

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $312,143

## Abstract

Abstract
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.

## Key facts

- **NIH application ID:** 10248380
- **Project number:** 5R01GM127673-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** David Bulkley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $312,143
- **Award type:** 5
- **Project period:** 2018-09-19 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10248380

## Citation

> US National Institutes of Health, RePORTER application 10248380, Regulated Mitochondrial Morphology (5R01GM127673-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10248380. Licensed CC0.

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