# Coordinated Repair and Regeneration of Defective Mitochondria

> **NIH NIH R37** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $446,523

## Abstract

Project Summary
Mitochondrial function declines during aging and is accelerated in age-associated diseases such as
Parkinson's and Alzheimer's. Thus, understanding how cells and organisms generate the appropriate
mitochondrial mass during development and maintain that mitochondrial network during aging is an essential
step to limiting pathologies associated with loss of mitochondrial function. Here, we aim to understand the
underlying mechanisms by which the transcription factor ATFS-1 and the mitochondrial unfolded protein
response (UPRmt) coordinate mitochondrial network biogenesis during normal development and the recovery
of the mitochondrial network via independently regulated functions of ATFS-1 in mitochondrial compartments
and the nucleus.
 Numerous components have been identified that promote replication of the mitochondrial genome and
transcription of nuclear-encoded genes that result in mitochondrial biogenesis. However, it remains unclear
how the appropriate amount of mitochondrial mass is achieved during development or cell specification, and
how the mitochondrial network is maintained over a cell or organisms lifetime. It also remains unknown if
mitochondrial genome (mtDNA) replication is coordinated with cell growth, physiology, or functional
heterogeneity within the compartments that comprise the mitochondrial network. Current dogma suggests that
mtDNA replication is entirely dependent on expression of several nuclear-encoded factors such as the mtDNA
polymerase. Despite functional heterogeneity within the mitochondrial network, compartment-specific
autonomy over mtDNA regulation is rarely considered.
 In this proposal, we aim to understand how ATFS-1 establishes the appropriate amount mitochondrial
mass during development, and maintains the mitochondrial network over an animals lifetime focusing on the
separate activities of nuclear ATFS-1, and the fraction of ATFS-1 that accumulates in dysfunctional
mitochondria and binds mtDNA. Lastly, we aim to understand the impact of an ATFS-1-mediated diapause that
occurs if the mitochondrial network is severely damaged during development. At the end of the funding period,
we hope to understand the endogenous strategies in place to establish and maintain the mitochondrial
network, to potentially develop strategies to promote or maintain a robust mitochondrial network.

## Key facts

- **NIH application ID:** 10371983
- **Project number:** 5R37AG047182-08
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Cole M Haynes
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $446,523
- **Award type:** 5
- **Project period:** 2015-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371983

## Citation

> US National Institutes of Health, RePORTER application 10371983, Coordinated Repair and Regeneration of Defective Mitochondria (5R37AG047182-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10371983. Licensed CC0.

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