# The role of sub-lethal mitochondrial apoptotic stress in cellular senescence

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2020 · $438,468

## Abstract

PROJECT SUMMARY/ABSTRACT
This application investigates the relationship between mitochondrial apoptotic stress,
senescence and aging. Cellular senescence is a well-established driver of tissue and
organismal aging, a process thought to be partly mediated via the induction of a chronic
Senescence-associated secretory phenotype (SASP). Consequently, there is great interest in
selectively targeting senescent cells as a strategy to promote healthy aging. Our work has
demonstrated that mitochondrial dysfunction is a hallmark of cellular senescence and a driver of
the SASP. Mitochondria are also major regulators of apoptosis, a process which involves
mitochondrial outer membrane permeability (MOMP) and subsequent release of cytochrome c
through the actions of the pro-apoptotic proteins BAX and BAK. We found that MOMP occurring
in a small subset of mitochondria without inducing cell-death, a process known as minority
MOMP (miMOMP) is a feature of cellular senescence and contributes to the SASP. We have
also observed that miMOMP leads to the release of cytosolic mtDNA which can engage the
cGAS/STING pathway, a major regulator of the SASP. These data led us to hypothesize that
miMOMP is a major contributor to the senescent phenotype and may be a novel target for
interventions aiming to counteract aging and age-related pathology.
We will conduct in vitro experiments in which we will explore the molecular mechanisms of why
miMOMP occurs during senescence and how it impacts on senescence and the SASP (aims 1
and 2). Finally, we will investigate the impact of genetic and pharmacologic interventions which
alleviate miMOMP during aging in vivo (aim 3). For that, we will unravel the relative impact of
conditional deletion of BAX/BAK (which drive miMOMP) and/or Apaf1 (essential for MOMP-
dependent caspase activation) during aging in vivo. Finally, we will test the effectiveness of
miMOMP-inhibiting drugs on improving key phenotypes in aging mice.
Our ultimate goal is to identify new interventions that target senescent cells to alleviate age-
related dysfunction.

## Key facts

- **NIH application ID:** 10026558
- **Project number:** 1R01AG068048-01
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Joao Passos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $438,468
- **Award type:** 1
- **Project period:** 2020-08-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10026558

## Citation

> US National Institutes of Health, RePORTER application 10026558, The role of sub-lethal mitochondrial apoptotic stress in cellular senescence (1R01AG068048-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10026558. Licensed CC0.

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