# Lysine Acetylation as Switch for Optic Atrophy 1 Inactivation

> **NIH NIH R01** · UNIVERSITY OF CENTRAL FLORIDA · 2021 · $482,538

## Abstract

Neurons depend on mitochondria to supply energy for processes such as synaptic transmission, channel
activity, and axonal transport. To meet the constantly changing energy demands of neurons, mitochondria
undergo frequent fission and fusion. Fission and fusion enhance respiration, ATP synthesis, Ca2+ homeostasis,
clearance of damaged organelles by mitophagy, neuronal function, and cell survival. However, excessive
fission and lack of fusion can cause mitochondrial fragmentation and is implicated in neurodegeneration.
 Mitochondrial fission and fusion are regulated by large GTPases of the dynamin family. Optic Atrophy 1
(OPA1) is required for mitochondrial inner membrane fusion and maintenance of cristae structure, mtDNA,
respiration, ATP synthesis, Ca2+ homeostasis, and neuronal cell survival. Significantly, autosomal dominant
mutations in OPA1 cause a spectrum of neurodegenerative disorders, including dominant optic atrophy (DOA),
characterized by degeneration of retinal ganglion cells (RGCs) and optic nerve axons. The majority of OPA1
missense mutations are located in the conserved GTPase (G) domain and interfere with normal OPA1 function
by dominant-negative mechanisms. Thus, inactivation of the G-domain is associated with disease
pathogenesis.
 While OPA1 mutations cause early-onset familial forms of neurodegenerative disease, it is unknown
whether OPA1 can also be inactivated in late-onset sporadic diseases. Remarkably, recent high-throughput
proteomic screens identified a major lysine acetylation site located in the G-domain and a hotspot of
pathogenic OPA1 mutations, predicting a critical functional role. The function of this posttranslational
modification (PTM) is unknown. In addition, research tools to investigate the significance of OPA1 lysine
acetylation are currently missing.
 Here, we will investigate whether lysine acetylation in the G-domain is a new PTM regulating OPA1
function. We will address the following questions: (1) Does acetylation inhibit OPA1 GTP hydrolysis? (2) Does
acetylated OPA1 inhibit mitochondrial fusion and function? (3) Does OPA1 acetylation play a causal role in
neuronal injury and cell death? Lysine acetylation might emerge as a novel mechanism of OPA1 inactivation
during aging and contribute to mitochondrial fragmentation and dysfunction in sporadic neurodegenerative
disorders. Modulating OPA1 acetylation might be a new neuroprotective strategy.

## Key facts

- **NIH application ID:** 10115053
- **Project number:** 5R01EY030104-02
- **Recipient organization:** UNIVERSITY OF CENTRAL FLORIDA
- **Principal Investigator:** Blaise Bossy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $482,538
- **Award type:** 5
- **Project period:** 2020-03-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115053

## Citation

> US National Institutes of Health, RePORTER application 10115053, Lysine Acetylation as Switch for Optic Atrophy 1 Inactivation (5R01EY030104-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10115053. Licensed CC0.

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