# Roles of mitochondrial dynamics and mtDNA in senescence

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $390,599

## Abstract

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.

## Key facts

- **NIH application ID:** 10791857
- **Project number:** 5R01GM144497-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** XIAO-FAN WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $390,599
- **Award type:** 5
- **Project period:** 2022-06-10 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10791857

## Citation

> US National Institutes of Health, RePORTER application 10791857, Roles of mitochondrial dynamics and mtDNA in senescence (5R01GM144497-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10791857. Licensed CC0.

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