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.

Public Health Relevance

A loss in mitochondrial function in the neuron triggers a signaling event that causes the remodeling of the behavior of mitochondria in other tissues. This response can be perpetuated throughout the lifespan of the organism. We propose a multi-pronged approach to study the ways in which the neuron senses mitochondrial stress, signals to other tissues, and propagates a sustained change in its behavior that can affect the survivorship of the entire animal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES021667-09
Application #
9764361
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Shaughnessy, Daniel
Project Start
2012-03-01
Project End
2022-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
9
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94710
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