# Biogenesis of the mitochondrial inner membrane Alzheimer's supplement

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $332,594

## Abstract

Abstract
 Mitochondrial dysfunction is a common contributing factor in neurodegenerative diseases including
Alzheimer’s (AD), Parkinson’s (PD), Huntington’s (HD), and amyotrophic lateral sclerosis (ALS). Mechanistic
studies in model systems are deficient because adequate tools are lacking. The proposal hypothesis is that
strategies to regulate selectively the removal or accumulation of dysfunctional mitochondria can delay or
prevent the onset of mitochondrial dysfunction that is an underpinning of neurodegenerative diseases,
particularly in Alzheimer’s disease. The team has characterized a collection of small molecule probes that
modulate mitochondrial protein translocation and strong preliminary evidence shows that manipulating these
protein import pathways regulates a selective pathway for autophagy of mitochondria, referred to as
mitophagy.
 The overalls goals of this supplement are (1) to characterize at a mechanistic level how this set of small
molecule probes regulate and induce various mitophagy pathways in cultured cell models including a neuronal
cell model for AD, and (2) to develop new zebrafish models for AD to determine how mitochondrial dysfunction
contributes to AD. The probes will subsequently be applied to the zebrafish models to determine how altering
mitophagy impacts neuronal function. This research will advance the field because (1) such mitochondrial-
specific probes have not been previously available and (2) the use of probes allows for selective control in the
induction and regulation of mitophagy pathways, which is difficult with current genetic models.
 To accomplish the proposal goals, two specific proposal aims will be undertaken: In Aim 1, cell models
including neural cells will be treated with the small molecules and mitophagy induction and progression will be
studied. In Aim 2, these experiments will be extended to zebrafish models that exhibit mitochondrial
dysfunction or aggregate accumulation in the neural system and the small molecule modulators will be tested.
 An outcome of this application is that studies will be advanced to dissect how mitophagy pathways are
regulated by modulation of mitochondrial protein import pathways. This supplement will have a broad impact
on AD and other neurodegenerative diseases, because a new set of probes will be verified that can be applied
to understand how mitochondrial dysfunction contributes to AD progression and/or attenuation.

## Key facts

- **NIH application ID:** 10712701
- **Project number:** 3R01GM061721-19S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Carla M Koehler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $332,594
- **Award type:** 3
- **Project period:** 2000-09-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10712701

## Citation

> US National Institutes of Health, RePORTER application 10712701, Biogenesis of the mitochondrial inner membrane Alzheimer's supplement (3R01GM061721-19S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10712701. Licensed CC0.

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