# IMPACTING MITOCHONDRIAL FUNCTION THROUGH ALTERED PROTEASE ACTIVITY

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2023 · $617,054

## Abstract

SUMMARY
Mitochondrial dysfunction is a pathologic hallmark in the onset and pathogenesis of nearly all
neurodegenerative diseases. One of the primary determinants in dictating mitochondrial function is the activity
of inner membrane (IM) proteases including the ATP-dependent AAA+ zinc metalloproteases YME1L and
AFG3L2 and the ATP-independent zinc metalloprotease OMA1. These proteases regulate many different
aspects of mitochondrial biology and function to protect mitochondria from pathologic insults. However,
imbalances in the activity of IM proteases induced by genetic or environmental factors are implicated in the
pathogenesis of etiologically-diverse diseases including many neurodegenerative disorders. Despite this, the
molecular mechanisms by which IM proteases regulate mitochondrial biology remain poorly understood. Here,
we are applying a structure-driven approach to determine the molecular mechanisms by which IM proteases
regulate mitochondria in the context of health and disease. We previously solved the first high-resolution
structures of the IM AAA+ proteases YME1 and AFG3L2. Our structures showed that these two proteases
employ a conserved nucleotide-driven, hand-over-hand mechanism to translocate substrates into a privileged
proteolytic chamber for proteolysis. Surprisingly, we also identified unique structural features of YME1 and
AFG3L2 that integrate into this conserved translocation mechanism to distinctly influence protease activity and
stability. Here, we hypothesize that these unique structural differences endow IM proteases with
different mechanistic and biologic functions important for their regulation of mitochondria. To address
this, we are using a combination of cryo-electron microscopy and cell biology to determine how structural
differences in IM AAA+ proteases influence their mechanochemical cycle and enable proteases to perform
distinct biological functions. This will reveal new insights into the molecular mechanisms by which IM AAA+
proteases regulate mitochondria in health and disease. Furthermore, we are extending this study utilizing both
functional genomic and structural approaches to establish a structure-function relationship that explains the
activation and proteolytic activity of the ATP-independent, stress-activated IM protease OMA1 – a protease
whose dysregulation is implicated in the pathologic mitochondrial dysfunction associated with many human
diseases. Through these efforts, we will define how IM proteases utilize distinct structural features to perform
the myriad of biological functions required for the proper regulation of mitochondrial proteostasis and function.
Furthermore, we will reveal new insights into the pathologic and potentially therapeutic implications of altered
mitochondrial IM protease activity in human disease and identify new opportunities to pharmacologically target
IM proteases to mitigate mitochondrial dysfunction associated with many neurodegenerative disorders.

## Key facts

- **NIH application ID:** 10692562
- **Project number:** 5R01NS095892-08
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Gabriel C Lander
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $617,054
- **Award type:** 5
- **Project period:** 2016-04-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10692562

## Citation

> US National Institutes of Health, RePORTER application 10692562, IMPACTING MITOCHONDRIAL FUNCTION THROUGH ALTERED PROTEASE ACTIVITY (5R01NS095892-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10692562. Licensed CC0.

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