# Determining the mechanism of mitochondrial outer membrane fusion

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $134,026

## Abstract

Project Summary
This proposal examines the mitofusin proteins, which catalyze both mitochondrial tethering and outer
membrane fusion. Mitochondrial shape is central to mitochondrial function and is closely linked to changes in
cellular physiology during development, stress, and aging. Mitochondrial fusion increases metabolic production,
protects against excessive degradation of mitochondria, reduces sensitivity of the cell to apoptotic stimuli and
allows functional complementation of damaged organelles. Compromised mitochondrial function and
decreased organelle connectivity are associated with neurodegeneration and other age-related diseases.
Furthermore, mutations in the genes encoding components of the mitochondrial fusion machine cause
peripheral neuropathy, optic atrophy, myopathy and ataxia. Both mitochondrial division and mitochondrial
fusion are mediated by conserved dynamin superfamily proteins. This diverse family of mechanochemical
GTPases couple self-assembly and conformational changes to membrane remodeling events throughout the
cell. Mitofusin is the mitochondrial outer membrane fusion machine and must assemble both in cis within a
single membrane, and in trans across two mitochondria. The molecular details, including of the composition of
these assemblies, the regulation of their formation and how they contribute to membrane tethering and fusion
are not known. We address these gaps in knowledge utilizing biochemical analyses of mitofusin function. In
Aim 1, we will elucidate mechanisms of allosteric regulation that control assembly of mitofusin into fusion-
competent complexes. Our collection of functional variants and novel approaches will provide a powerful tool
in dissecting the contribution of each mitofusin functional domain to cis oligomerization and trans complex
formation. Our work characterizing CMT2A-associated variants of mitofusin revealed that molecular defects of
mitofusin can be compensated for by cytosolic factors in cells. In Aim 2, we use a reductionist approach that
combines cell biology, biochemistry, and reconstituted assays developed in my lab to determine how the
cytosolic mitofusin effector Bax alters mitofusin assembly to regulate mitochondrial fusion. This research
program draws on our strengths in cellular and biochemical analysis of mitochondrial biology and will yield
fundamental insights not only for mitochondrial dynamics but for the mechanisms through which dynamin
superfamily proteins in general operate.

## Key facts

- **NIH application ID:** 11032697
- **Project number:** 3R01GM118509-08S1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Suzanne C Hoppins
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $134,026
- **Award type:** 3
- **Project period:** 2017-02-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11032697

## Citation

> US National Institutes of Health, RePORTER application 11032697, Determining the mechanism of mitochondrial outer membrane fusion (3R01GM118509-08S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11032697. Licensed CC0.

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