Wednesday, July 2, 2025 7/2/2025

Roles of mitochondrial dynamics and mtDNA in senescence

Award Number: R01GM144497
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: 06/10/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Roles of mitochondrial dynamics and mtDNA in senescence - This proposal's long-term objective is to provide a fundamental mechanistic understanding of the role of nucleus vs. mitochondria in the activation of the senescence program. Senescence is a central cellular defense mechanism that removes damaged cells to maintain tissue integrity and prevent tumorigenesis. The accumulation of senescent cells, which express a copious amount of inflammatory cytokines, termed senescence-associated secretory phenotype (SASP), is a significant contributing factor to organismal aging. In the last decade, studies have identified the disruption of nuclear membrane (lamina) integrity and subsequent release of nuclear DNA (nDNA) to the cytosol as the primary trigger of senescence and premature aging, progeria. On the other hand, experimental evidence has long implied mitochondria in senescence and aging. However, the exact role of mitochondria in senescence remains unknown. We have found that during senescence, mitochondrial DNA (mtDNA) contents were elevated significantly and mitochondria undergo elaborate fusion. Gene expression analysis of senescent cells revealed coordinated upregulation of ABAT and RRM2B, two genes that are required for mtDNA synthesis and maintenance. These genes are also elevated in mice of old age. We found that pharmacological inhibition of mtDNA synthesis suppressed SASP but did affect senescence-associated growth arrest. These findings uncover a unique signaling role of mtDNA in SASP and coordinated mitochondrial remodeling during senescence. This proposal aims to delineate the functional significance of the nuclear and mitochondrial pathway in SASP associated with senescence and aging and investigate the regulation and roles of mitochondrial dynamics in the activation of SASP.


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 = $390,464 )
2025	2025	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	000	4	4/15/2025	NON-COMPETING CONTINUATION	$390,464
														Subtotal = $390,464

Issue Date FY: 2024 ( Subtotal = $390,599 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	000	3	3/20/2024	NON-COMPETING CONTINUATION	$351,539
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	001	3	7/23/2024	NON-COMPETING CONTINUATION	$39,060
														Subtotal = $390,599

Issue Date FY: 2023 ( Subtotal = $494,399 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	001	2	8/1/2023	SUPPLEMENT FOR EXPANSION	$103,752
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	000	2	2/17/2023	NON-COMPETING CONTINUATION	$390,647
														Subtotal = $494,399

Issue Date FY: 2022 ( Subtotal = $390,761 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	1	6/9/2022	NEW	$390,761
														Subtotal = $390,761

Grand Total All Awards = $1,666,223

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Roles of mitochondrial dynamics and mtDNA in senescence

Award Number: R01GM144497

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: 06/10/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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