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Regulation of mtDNA replication and repair by mitochondrial Hsp70 chaperone, Mortalin

Award Number: R15GM139104
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Regulation of mtDNA replication and repair by mitochondrial Hsp70 chaperone, Mortalin - Abstract Defects of the human mitochondrial genome maintenance result in the accumulation of mutations that give rise to a broad spectrum of degenerative disorders, involving multiple organs and systems of the human body. Here we propose to investigate critical gaps of knowledge in our comprehension of two key processes of the genome maintenance, namely replication and repair of mitochondrial DNA (mtDNA). Although the core mitochondrial replisome, comprising DNA polymerase γ (Polγ), Twinkle helicase, and mtSSB, has been established, in vivo ~95% of all replication events initiated at the origin are terminated prematurely, at the termination associated sequence (TAS). This implies that TAS is a critical check point for the process. However, the mechanism regulating/terminating the replisome activity at TAS remains unknown since its discovery in the early 80s. Insight into the molecular basis of this step of mtDNA replication could advance the field towards harnessing control over the process in clinical settings. Fine-tuning mtDNA copy number is a sought-after therapeutic strategy for many conditions associated with mtDNA, including rare mitochondrial disorders (e.g., Alpers syndrome), as well as prominent neurodegenerative diseases (Parkinson’s, Alzheimer’s, multiple sclerosis, ALS), various types of cancer, and natural human aging. Here we propose that the mitochondrial Hsp70 chaperone (Mortalin) in cooperation with its Hsp40 partner (Tid1) serve as the regulatory factors controlling the activity of the replisome at the TAS site. So far, we have gathered compelling preliminary results indicating that the system enhances mtDNA synthesis in cultured human cells and in functional in vitro assays, by stimulating the activity of Polγ. We now aim to provide a mechanistic explanation of the observed effects, by interrogating the physical and functional interactions of the chaperones with the replisome. In addition, our preliminary work hinted that Mortalin may also serve as the regulator of the base excision repair pathway of mtDNA repair, which is the ‘first line’ of defense against highly reactive radicals continuously produced in mitochondria. The proposed project will address major knowledge gaps in the field of mtDNA maintenance, and the prospective outcomes of this work will advance the field towards novel therapeutic strategies.


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: 2026 ( Subtotal = $555,000 )
2026	2026	UNIVERSITY OF NORTH FLORIDA	1 UNF DR	JACKSONVILLE	FL	32224	DUVAL	USA	Biomedical Research and Research Training	001	3	7/7/2026	COMPETING CONTINUATION	$555,000
2026	2021	UNIVERSITY OF NORTH FLORIDA	1 UNF DR	JACKSONVILLE	FL	32224	DUVAL	USA	Biomedical Research and Research Training	000	2	4/24/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $555,000

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2021	AUBURN UNIVERSITY MONTGOMERY	7430 EAST DR LIBRARY TOWER 700	MONTGOMERY	AL	36117	MONTGOMERY	USA	Biomedical Research and Research Training	000	1	1/20/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	UNIVERISTY OF NORTH FLORIDA	1 U N F DR	JACKSONVILLE	FL	32224	DUVAL	USA	Biomedical Research and Research Training	000	2	7/19/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $16,567 )
2023	2022	AUBURN UNIVERSITY	7430 EAST DR 700 LIBRARY TOWER	MONTGOMERY	AL	36117	MONTGOMERY	USA	Biomedical Research and Research Training	001	1	8/4/2023	SUPPLEMENT FOR EXPANSION	$0
2023	2021	UNIVERISTY OF NORTH FLORIDA	1 U N F DR	JACKSONVILLE	FL	32224	DUVAL	USA	Biomedical Research and Research Training	002	2	8/7/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$210,164
2023	2021	AUBURN UNIVERSITY	7430 EAST DR 700 LIBRARY TOWER	MONTGOMERY	AL	36117	MONTGOMERY	USA	Biomedical Research and Research Training	000	1	8/3/2023	NEW	-$193,597
														Subtotal = $16,567

Issue Date FY: 2022 ( Subtotal = $100,000 )
2022	2022	AUBURN UNIVERSITY	7430 EAST DR 700 LIBRARY TOWER	MONTGOMERY	AL	36117	MONTGOMERY	USA	Biomedical Research and Research Training	000	1	5/24/2022	SUPPLEMENT FOR EXPANSION	$100,000
														Subtotal = $100,000

Issue Date FY: 2021 ( Subtotal = $403,493 )
2021	2021	AUBURN UNIVERSITY	7430 EAST DR 700 LIBRARY TOWER	MONTGOMERY	AL	36117	MONTGOMERY	USA	Biomedical Research and Research Training	000	1	8/19/2021	NEW	$403,493
														Subtotal = $403,493

Grand Total All Awards = $1,075,060

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Regulation of mtDNA replication and repair by mitochondrial Hsp70 chaperone, Mortalin

Award Number: R15GM139104

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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