# Protective Role of Mitochondrial CHCHD10 in Alzheimer's Disease through MAM and Mitophagy Mechanisms.

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $630,595

## Abstract

Project Summary
Dysfunctions in mitochondria and mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) are
associated with the accumulation of amyloid β (Aβ) and hyperphosphorylated tau in Alzheimer's disease (AD).
Mitochondrial protein, CHCHD10, plays a pivotal role in governing various mitochondrial functions, including
respiration, genome stability, dynamics, cristae organization, and oxidative phosphorylation. In our preliminary
study, CHCHD10 declines in the brains of APP/PS1 mice and human AD patients, which negatively correlates
with Ab levels. Restoration of CHCHD10 in APP/PS1 mice reduces AD pathogenesis in vivo. In transfected cells,
wild-type CHCHD10 promotes mitochondrial respiration as well as mitophagy and autophagy via PINK1/Parkin
and p62/LC3 pathways. In addition, increasing CHCHD10 mitigates MAM hyperactivity in AD. We have identified
specific small DNA oligos (antagoNATs) derived from CHCHD10 natural antisense transcripts (NATs) that
effectively augment CHCHD10 levels in both mouse and human cells. Our preliminary study shows that
CHCHD10 antagoNATs increase endogenous CHCHD10 protein both in vivo in mice brains and in vitro in human
cell lines. This study has two principal objectives: (1) to evaluate the therapeutic potential of CHCHD10
antagoNATs by assessing their protective effects on these phenotypes in APP/PS1 mice and human neurons,
and (2) to delineate the intricate interplay between CHCHD10, MAM, and mitophagy, thus elucidating their
collective role in ameliorating AD pathogenesis.
Successful conclusion of this study will: (1) facilitate the CHCHD10 antagoNATs as a therapeutic strategy for
AD; (2) provide a mechanistic basis and insights into CHCHD10-associated mechanisms in AD.

## Key facts

- **NIH application ID:** 10853761
- **Project number:** 1R01AG086365-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Tian Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $630,595
- **Award type:** 1
- **Project period:** 2024-08-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10853761

## Citation

> US National Institutes of Health, RePORTER application 10853761, Protective Role of Mitochondrial CHCHD10 in Alzheimer's Disease through MAM and Mitophagy Mechanisms. (1R01AG086365-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10853761. Licensed CC0.

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