# BIOGENESIS OF THE MITOCHONDRIAL INNER MEMBRANE

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $429,221

## Abstract

SUMMARY
 Mitochondrial dysfunction is a common contributing factor to degenerative diseases, including the
neural and muscular systems; yet mechanistic studies in mammals are limited because adequate tools and
approaches are lacking. Moreover, a greater understanding of the protein translocation mechanisms in model
organisms such as S. cerevisiae and zebrafish is needed, because protein translocation is linked to
metabolism, signaling, and mitochondrial quality control and stress pathways such as mitophagy. Long-term,
modulating mitochondrial protein import pathways therefore is a potential target for treating diseases.
 The overall goals of this proposal are (1) to increase our mechanistic understanding of protein import
pathways into mitochondria in both yeast and mammalian cells and (2) to understand how defects in protein
translocation contribute to disease. Attenuating protein translocation pathways can alter the location of
mitochondrial proteins that are dual-localized (located to mitochondria and another compartment), change
mitochondrial stress pathways, and induce selective turnover of mitochondria via mitophagy. However, there is
a critical gap in developing small molecule probes with specificity for modulating mitochondrial protein import
specifically in mammalian cells while minimizing off-target effects.
 Three specific study aims are proposed to accomplish these goals. In Aim 1, a new cell based screen in
mammalian cells to identify modulators for all mitochondrial protein import pathways and specific cargo will be
implemented. In Aim 2, a series of experimental approaches will be used to characterize specificity of the
probes, to minimize off-target effects in mammalian cells and yeast, with the goal of developing specific
probes. In Aim 3, existing and new small molecules will be characterized in mechanistic studies, particularly
focusing on how defects in protein import alter mitochondrial stress pathways in mitophagy.
 In addition to increasing fundamental knowledge about the mechanisms of protein translocation in
mitochondria, this application may have a broad impact on public health because our approach will provide
new tools that will provide a strategy for developing therapeutics for diseases that can be modified by
attenuating protein translocation.

## Key facts

- **NIH application ID:** 10521919
- **Project number:** 2R01GM061721-18A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Carla M Koehler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $429,221
- **Award type:** 2
- **Project period:** 2000-09-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10521919

## Citation

> US National Institutes of Health, RePORTER application 10521919, BIOGENESIS OF THE MITOCHONDRIAL INNER MEMBRANE (2R01GM061721-18A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10521919. Licensed CC0.

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