# Project 5: Unraveling mechanisms for neurological diseases caused by ATAD3A mutations

> **NIH NIH P20** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2021 · $393,758

## Abstract

PROJECT SUMMARY/ABSTRACT 
Mitochondrial dysfunction is a pathological feature of many neurodegenerative diseases. We recently discovered 
that mutations in the mitochondrial protein ATAD3A (ATPase family, AAA domain containing 3A) cause HAREL- 
YOON syndrome, a disease characterized by peripheral neuropathy, optic atrophy, cardiomyopathy, and brain 
malformation. ATAD3A is implicated in other neurological genetic diseases, including hereditary spastic 
paraplegia, and congenital pontocerebellar hypoplasia, with abnormal cholesterol metabolism suggested as an 
underlying cause. Although ATAD3A is known to influence mitochondrial biology and lipid metabolism, how 
mutations in ATAD3A cause disease is unknown. There is an urgent need to fill this knowledge gap in order to 
prevent or treat ATAD3A-associated and other mitochondrial diseases, most of which have no known cure. 
 Our long-term goal is to discover new therapeutic targets and strategies for mitochondrial diseases. The 
objective of our proposal is to uncover the mechanisms by which ATAD3A controls mitochondrial functions, using 
Drosophila and ATAD3A patient-derived induced pluripotent stem cells. Our CENTRAL HYPOTHESIS is that 
ATAD3A regulates mitochondrial membrane lipid homeostasis, and thus mitochondrial membrane dynamics, 
mitochondrial DNA (mtDNA) replication, and lipid metabolism, based on the following compelling evidence. First, 
ATAD3A plays a role in the formation of ER-mitochondria contact sites (EMCS) which are essential for import 
and synthesis of phospholipids. Second, ATAD3A is essential for importing cholesterol into mitochondria as well 
as maintaining cholesterol-rich mitochondria membrane structures. Lastly, patients carrying ATAD3A mutations 
exhibit increased 3-methylglutaconic acid excretion, which is often caused by a deficiency in mitochondrial 
respiratory complexes secondary to defects in cardiolipin remodeling. We expect that mechanistic insight into 
the consequences of ATADA3 mutations derived from our studies will reveal unanticipated therapeutic targets 
for prevention or treatment of a variety of mitochondrial diseases. We will test our central hypothesis by 
performing the following Specific Aims: (1) Elucidate how ATAD3A regulates mitochondrial membrane dynamics; 
(2) Determine how ATAD3A promotes mtDNA replication in neurons; and (3) Determine how ATAD3A regulates 
proper heart function. 
Upon conclusion of our studies, we expect to uncover how ATAD3A modulates mitochondria membrane 
dynamics, biogenesis, and heart function. Understanding how ATAD3A links diverse aspects of mitochondrial 
biology is expected to have a positive impact by revealing the molecular basis, as well as novel therapeutic 
targets and strategies for ATAD3A-associated diseases and other disorders caused by mitochondrial 
dysfunction.

## Key facts

- **NIH application ID:** 10225578
- **Project number:** 5P20GM103636-09
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Wan Hee Yoon
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $393,758
- **Award type:** 5
- **Project period:** 2013-03-01 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225578

## Citation

> US National Institutes of Health, RePORTER application 10225578, Project 5: Unraveling mechanisms for neurological diseases caused by ATAD3A mutations (5P20GM103636-09). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10225578. Licensed CC0.

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