# Modulation of mitochondrial biogenesis by the Integrated Stress Response (ISR)

> **NIH NIH F30** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $54,344

## Abstract

Project Summary
Mitochondrial function declines during aging. The dysfunction is accelerated in age-associated diseases such
as Alzheimer’s Disease and Parkinson’s Disease. Thus, therapeutic approaches to maintain or recover
mitochondrial function may promote healthy aging or slow age-associated disease progression. Recently, we
have shown that the mitochondrial network expansion that occurs during development is an emergent property
of the synthesis of highly expressed mitochondrial proteins. Increased mitochondrial import of the highly
expressed mitochondrial proteins outcompete the transcription factor ATFS-1, preventing it from entering
mitochondria. This allows ATFS-1 to traffic to the nucleus and activate a mitochondrial network expansion
transcription program known as UPRmt. These findings suggest an interplay between protein synthesis,
mitochondria protein import capacity, and mitochondrial network expansion.
 The Integrated Stress Response (ISR) is a translation control pathway that reduces overall protein
synthesis while preferentially increases translation of ATF-4 in response to diverse stressors including amino
acid depletion, ER dysfunction and mitochondrial perturbations. The ISR is mediated by 4 kinases (3 in C.
elegans) that all phosphorylate the translation initiation factor eIF2α, which in turn modulates protein synthesis.
While considerable work has demonstrated that the ISR is active in response to mitochondrial perturbation, the
functional outputs of the ISR related to mitochondrial biology remain unknown. I have obtained or generated
several C. elegans strains in which the ISR is impaired. Quite surprisingly, these worms have increased
mitochondrial mass and mitochondrial genomes. Intriguingly, these animals also live significantly longer than
wildtype worms, suggesting that increased mitochondrial mass is sufficient to extend organismal lifespan. I
hypothesize that the ISR matches mitochondrial network expansion with the physiological and environmental
inputs that activate the ISR by antagonizing ATFS-1 function. Here, I focus on the role of ISR-dependent
translation attenuation or ATF-4 synthesis as direct or indirect regulators of ATFS-1-dependent transcription via
the following aims.
1. Determine the mechanisms by which the ISR regulates ATFS-1-dependent mitochondrial biogenesis.
2. Elucidate the mechanisms by which the ISR modulates longevity and healthspan.

## Key facts

- **NIH application ID:** 10827979
- **Project number:** 5F30AG077833-03
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Sookyung Kim
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $54,344
- **Award type:** 5
- **Project period:** 2022-05-05 → 2027-05-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10827979

## Citation

> US National Institutes of Health, RePORTER application 10827979, Modulation of mitochondrial biogenesis by the Integrated Stress Response (ISR) (5F30AG077833-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10827979. Licensed CC0.

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