# Coordinating mitochondrial network expansion and longevity via the Integrated Stress Response (ISR)

> **NIH NIH R56** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $335,000

## Abstract

Project Summary
Mitochondrial function declines during normal aging and is accelerated in age-associated diseases such as
Parkinson’s and Alzheimer’s. Thus, understanding how cells and organisms regulate mitochondrial network
expansion during growth to meet cell-specific requirements, and maintain that mitochondrial network during
aging, are essential steps to limiting pathologies associated with mitochondrial dysfunction and prolonging
lifespan. Our published findings indicate that the mitochondrial network expansion that occurs during
development is an emergent property of the synthesis of highly expressed mitochondrial proteins and ATFS-1-
dependent mitochondrial UPR activation. Increased import flux of highly expressed mitochondrial proteins
excludes the transcription factor ATFS-1 from mitochondria resulting in nuclear trafficking and UPRmt activation,
which includes a mitochondrial biogenesis program. These findings suggest an interplay between protein
synthesis, mitochondrial protein import capacity, and mitochondrial network expansion.
 Here, we examine the role of a translation control pathway known as the Integrated Stress Response
(ISR) on the regulation of mitochondrial network expansion during development and aging. Surprisingly, our
preliminary findings indicate that worms with an impaired ISR have substantially more mitochondrial biomass
and increased longevity, suggesting potential approaches to recover mitochondrial function in aged cells. We
hypothesize that the ISR provides two functions during cell growth; 1) it regulates protein synthesis rates via
eIF2α phosphorylation so as not to overwhelm network assembly and expansion, and 2) increases ATFS-1/ATF5
expression to activate a transcriptional program to facilitate mitochondrial network expansion. While considerable
work has demonstrated that the ISR is active during mitochondrial dysfunction, the functional outputs of the ISR
as related to the mitochondrial network remain unclear. We will test this hypothesis in both C. elegans and
mammalian cell culture via the following aims:
1. The role of the ISR in regulating mitochondrial network expansion in C. elegans.
2. Determine the impact of ISR-mediated translation regulation on C. elegans longevity.
3. Elucidate the role of the ISR in establishing a functional mitochondrial network in mammalian cells.

## Key facts

- **NIH application ID:** 10589511
- **Project number:** 1R56AG075204-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Cole M Haynes
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $335,000
- **Award type:** 1
- **Project period:** 2022-06-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10589511

## Citation

> US National Institutes of Health, RePORTER application 10589511, Coordinating mitochondrial network expansion and longevity via the Integrated Stress Response (ISR) (1R56AG075204-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10589511. Licensed CC0.

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