# MAINTENANCE OF MITOCHONDRIAL PROTEIN FOLDING AS AN AGING EFFECTOR

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $343,375

## Abstract

Project Summary
Mitochondrial function declines with age and is exacerbated in disease states such as Parkinson's.
One potential cause of the mitochondrial decline is the propagation of deleterious mitochondrial
genomes (mtDNAs) throughout an organism's lifetime as has been observed in individual muscle
cells or dopaminergic neurons. mtDNAs only encode respiratory chain and ATP synthase
components and thus lesions result in oxidative phosphorylation (OxPhos) deficiency. Because
mtDNAs exist at 100s-1000s of copies per cell, a lesion in a single genome is well tolerated.
However, if the deleterious genome accumulates to greater than ~60%, pathology related to
OxPhos dysfunction ensues including cell degeneration and death. It is currently unclear how
deleterious mtDNAs are maintained, how they are propagated and ultimately why they are toxic.
One mechanism by which cells respond to OxPhos deficiency is by activating the mitochondrial
unfolded protein response (UPRmt), which initiates a mitochondrial repair and recovery program.
We have found that UPRmt activation provides protection against OxPhos deficiencies caused by
nuclear mutations in OxPhos genes or against bacterial derived toxins (P. aeruginosa produces
cyanide for example). Our surprising preliminary data indicate that the UPRmt is required to
maintain and propagate deleterious mtDNAs in a C. elegans model of heteroplasmy. Therefore, we
hypothesize that deleterious mtDNAs are selfish, or parasitic, and take advantage of an
endogenous stress response program in place to repair and respond to mitochondrial dysfunction.
Here, we plan to examine the consequences of UPRmt activation and deleterious mtDNA
propagation as a contributor to age-associated mitochondrial dysfunction.

## Key facts

- **NIH application ID:** 9923550
- **Project number:** 5R01AG040061-11
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Cole M Haynes
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,375
- **Award type:** 5
- **Project period:** 2016-09-30 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9923550

## Citation

> US National Institutes of Health, RePORTER application 9923550, MAINTENANCE OF MITOCHONDRIAL PROTEIN FOLDING AS AN AGING EFFECTOR (5R01AG040061-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9923550. Licensed CC0.

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