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Lysine Acetylation as Switch for Optic Atrophy 1 Inactivation

Award Number: R01EY030104
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2020
PERIOD OF PERFORMANCE END DATE: 05/07/2024

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Lysine Acetylation as Switch for Optic Atrophy 1 Inactivation - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$345,266 )
2025	2023	THE UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Vision Research	000	4	11/25/2024	NON-COMPETING CONTINUATION	-$345,266
														Subtotal = -$345,266

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	THE UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Vision Research	000	4	4/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $400,351 )
2023	2023	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Vision Research	000	4	1/27/2023	NON-COMPETING CONTINUATION	$400,351
														Subtotal = $400,351

Issue Date FY: 2022 ( Subtotal = $423,188 )
2022	2022	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Vision Research	001	3	1/31/2022	NON-COMPETING CONTINUATION	$423,188
2022	2021	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Vision Research	000	2	10/28/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $423,188

Issue Date FY: 2021 ( Subtotal = $482,538 )
2021	2021	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Vision Research	001	2	3/12/2021	NON-COMPETING CONTINUATION	$34,821
2021	2021	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Vision Research	000	2	1/27/2021	NON-COMPETING CONTINUATION	$447,717
														Subtotal = $482,538

Issue Date FY: 2020 ( Subtotal = $516,083 )
2020	2020	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CNTRL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Vision Research	000	1	2/26/2020	NEW	$516,083
														Subtotal = $516,083

Grand Total All Awards = $1,476,894

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Lysine Acetylation as Switch for Optic Atrophy 1 Inactivation

Award Number: R01EY030104

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2020

PERIOD OF PERFORMANCE END DATE: 05/07/2024

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