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

> **NIH NIH P20** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2020 · $331,482

## 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:** 9997971
- **Project number:** 5P20GM103636-08
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Wan Hee Yoon
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $331,482
- **Award type:** 5
- **Project period:** 2013-03-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997971

## Citation

> US National Institutes of Health, RePORTER application 9997971, Project 5: Unraveling mechanisms for neurological diseases caused by ATAD3A mutations (5P20GM103636-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9997971. Licensed CC0.

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