# REGULATION OF MITOCHONDRIAL DNA-MEDIATED SIGNALING AND ITS CONTRIBUTION TO CELLULAR AND ORGANISMAL AGING

> **NIH NIH F31** · YALE UNIVERSITY · 2020 · $45,520

## Abstract

Project Summary:
Mitochondria are essential to life, as they not only produce the energy our cells need to maintain cellular
homeostasis but are also involved in cellular signaling and immunity. Mitochondrial dysfunction has been
implicated in the pathogenesis of various diseases. In addition, mitochondrial DNA (mtDNA), which can escape
the mitochondria in circumstances that are still being elucidated, can activate cytoplasmic DNA sensors to
trigger an immune response. Circulating mtDNA increases with age, indicating that release of mtDNA from the
mitochondria and the subsequent activation of immune signaling may be a physiologically relevant process
that may contribute to the development of age-related pathology. Our lab discovered that decreased levels of
the mitochondrial protein Transcription Factor A, mitochondrial (TFAM), which functions in packaging mtDNA
inside the mitochondria, leads to enhanced release of mtDNA into the cytoplasm. TFAM protein levels have
been shown to decrease with age in various animal models, but the consequences of increased cytoplasmic
mtDNA on the aging process has not been explored.
Our lab has developed a Tfam heterozygous knock-out (Tfam+/-) mouse model of enhanced mtDNA release.
Cells and tissues from these mice show no significant differences in oxygen consumption rates or mtDNA
encoded transcripts when compared to wild-type (WT) mice despite having a 50% depletion of mtDNA and
enhanced mtDNA release into the cytoplasm.
Mouse embryonic fibroblasts and bone-marrow derived macrophages will be generated from WT and Tfam+/-
mice to test the activation of autophagy in response to cytoplasmic mtDNA. Since autophagy proteins have
been shown to regulate the activity of the cGAS-STING pathway when bacterial DNA acts as a trigger, the
dependency of both cGAS activation, STING activation, and the presence of various autophagy proteins will be
tested to fully elucidate the mechanism by which autophagy is activated in this context.
Activation of cGAS is a key process in the activation of the senescence program. Cellular senescence
underlies many age-related pathologies. Mouse primary lung fibroblasts will be generated from WT and Tfam+/-
mice to test the effect of mtDNA-mediated signaling on the rate of onset of senescence. In addition, the onset
of senescence in vivo and the contribution of mtDNA-mediated signaling to the development of age-related
pathology will be investigated using a well-established frailty scale.
This project will shed light on the mechanisms by which mtDNA-mediated signaling is regulated, and the
contribution of mtDNA pro-inflammatory signaling to the progression of age-related pathology. Understanding
the molecular biology underlying the aging-process will help identify novel therapeutic interventions to extend
healthy lifespan.

## Key facts

- **NIH application ID:** 9812752
- **Project number:** 5F31AG062099-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Alva Gabriela Sainz
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2018-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9812752

## Citation

> US National Institutes of Health, RePORTER application 9812752, REGULATION OF MITOCHONDRIAL DNA-MEDIATED SIGNALING AND ITS CONTRIBUTION TO CELLULAR AND ORGANISMAL AGING (5F31AG062099-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9812752. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*