# Neuroendocrine Coordination of Mitochondrial Stress Signaling and Proteostasis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $343,617

## Abstract

Mitochondrial dysfunction is a primary consequence of nearly all age-onset neurodegenerative diseases.
Across eukaryotic species, however, mild mitochondrial stress can have beneficial effects on the lifespan of
organisms. Studies on the roles of mitochondria in the aging process have suggested that reduced
mitochondrial function during a critical window of development in the nematode C. elegans is sufficient to
extend the lifespan of the organism. Mitochondrial stress during this time results in a massive and persistent
restructuring in gene expression patterns, as evidenced by analyses of long-lived mitochondrial mutant
animals. This sustained response to an early metabolic stress may allow the organism to adapt its adult
metabolism to match predicted states of nutrient availability.
Previously, we reported that reduced mitochondrial function specifically in the neurons was sufficient to extend
the lifespan of the nematode C. elegans. Mild neuronal mitochondrial stress also caused an upregulation in
mitochondrial stress signaling across distal tissues of the organism. We now report evidence for the
requirement of a class of metabolic neurotransmitters in the dissemination of perceived mitochondrial stress.
We also observe a neuron-specific epigenetic remodeling in response to mitochondrial dysfunction. We
hypothesize that, after sensing metabolic stress, neurons transcriptionally remodel their gene expression
patterns by activating a class of neuron-specific chromatin modifying enzymes. Transcriptional changes in the
neurons then initiate a downstream neuroendocrine signaling event that is capable of activating mitochondrial
stress responsive pathways across tissues and organs. This cascade of responses collectively serves to
increase the metabolic fitness and lifespan of the organism.

## Key facts

- **NIH application ID:** 9942432
- **Project number:** 5R01ES021667-10
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Andrew G Dillin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,617
- **Award type:** 5
- **Project period:** 2012-03-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9942432

## Citation

> US National Institutes of Health, RePORTER application 9942432, Neuroendocrine Coordination of Mitochondrial Stress Signaling and Proteostasis (5R01ES021667-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9942432. Licensed CC0.

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