# Defining the Allosteric Network of Stress-Responsive Mitochondrial Protease OMA1

> **NIH NIH F31** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $33,036

## Abstract

PROJECT SUMMARY
Systems to identify, endure, and respond to stress are critical for longevity and cellular function. As the hub of
bioenergetic processes, mitochondria have an array of stress tolerance systems, one of which is comprised of
proteases localized to the inner mitochondrial membrane (IMM). IMM proteases acutely manage stress, but
chronic imbalances in the activity of IMM proteases contribute to mitochondrial dysfunction associated with
ageing and etiologically-diverse age-associated diseases including many neurodegenerative disorders and
cardiomyopathy. Remarkably, interventions to rescue and restore balance to IMM protease activity have
demonstrated therapeutic benefit for mitigating pathologic mitochondrial dysfunction implicated in both acute and
chronic age-associated diseases as well as lifespan extension. This multimodal therapeutic value has led to
significant interest in defining the molecular mechanisms that drive IMM protease function. One central stress
responsive IMM protease that remains understudied is the ATP-independent zinc metalloprotease OMA1.
Basally inactive, OMA1 is activated in response to mitochondrial insults through a poorly defined mechanism.
Active OMA1 site-specifically cleaves select IM substrates to protect mitochondria from acute mitochondrial
insults through modulation of morphology and the activation of stress-responsive transcription factors. Despite
the central role of OMA1 in mounting a mitochondrial stress response and its high therapeutic value, no structural
information of OMA1 activation or proteolytic activity has been defined. Here, we integrate cryo-EM structure
determination (Aim 1) and deep mutational scanning (Aim 2) to establish the first structure-function relationship
for OMA1 activation and proteolytic activity. Through these efforts, we will define the molecular mechanism of
OMA1 activation and proteolysis. This will reveal new insights into OMA1-dependent regulation of mitochondrial
proteostasis and function and establish a structural basis to develop new strategies to therapeutically target
OMA1 to mitigate pathologic mitochondrial dysfunction associated with ageing and ageing-associated
neurodegeneration and cardiomyopathy.

## Key facts

- **NIH application ID:** 10141518
- **Project number:** 1F31AG071162-01
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Albert Sanghoon Song
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $33,036
- **Award type:** 1
- **Project period:** 2021-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10141518

## Citation

> US National Institutes of Health, RePORTER application 10141518, Defining the Allosteric Network of Stress-Responsive Mitochondrial Protease OMA1 (1F31AG071162-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10141518. Licensed CC0.

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