A decline in mitochondrial and respiratory chain function occurs over time and likely contributes to the aging process as well as to the onset of numerous age-associated diseases. Many factors contribute including mitochondrial and nuclear genome mutations in respiratory chain genes as well as the degeneration of the respiratory chain complexes themselves. A prominent hypothesis is that by simply inducing cells to increase mitochondrial biogenesis, many of the cellular defects and disease symptoms can be alleviated. In this proposal, we aim to understand the intrinsic pathways employed by cells to adapt metabolism as well as promote respiratory chain biogenesis during age-associated mitochondrial dysfunction. We have demonstrated that the mitochondrial unfolded protein (UPRmt) is regulated by the transcription factor ATFS-1, which during mitochondrial stress leads to the transcriptional induction of protective genes including mitochondrial chaperones and proteases, anti-ROS machinery, mitochondrial fission and autophagy machinery. More recently, we have found that in addition to adapting mitochondrial proteostasis, the UPRmt also has a prominent role in adapting metabolism to promote respiratory chain biogenesis within stressed mitochondria while inducing the glycolysis pathway to maintain ATP levels. In this proposal, we aim to understand the interaction of the UPRmt with a separate, recently discovered, mitochondrial protective stress response. We have identified a separate transcription factor, ZIP-3, that is simultaneously activated during mitochondrial stress that specifically induces transcription of respiratory chain genes. Interestingly, our preliminary data suggest that ATFS-1 fine-tunes respiratory chain transcription by antagonizing ZIP-3, to match the protein-folding capacity in the stressed organelle and promote complex assembly. We anticipate a complete understanding of the interactions between these two pathways will reveal strategies cells employ to increase mitochondrial biogenesis during suboptimal conditions; a scenario potentially quite different than that found during development or normal cell division.
Aim 1 is to determine how ATFS-1 adjusts respiratory chain transcription to promote complex assembly during stress. Our preliminary data suggest a novel form of regulation where ATFS-1 binds directly to promoters in both genomes.
Aim 2 is to understand how the recently identified transcription factor ZIP-3 is regulated during mitochondrial stress to induce respiratory chain gene transcription.
Aim 3 is to understand how these two pathways integrate during normal aging as well as age- associated stress to promote respiratory chain biogenesis and impact longevity.

Public Health Relevance

The decline in mitochondrial function caused by a number of factors including respiratory chain dysfunction is a primary cause of aging and age-associated diseases such as Parkinson's. Many have hypothesized that by simply increasing mitochondrial biogenesis the age and disease-associated defects will be mitigated, however strategies to implement this approach are unclear, particularly in aged or diseased cells. In this proposal, we aim to understand how two recently identified intrinsic signaling pathways interact to promote mitochondrial and respiratory chain biogenesis during age-associated stress, which will hopefully yield novel therapeutic insight.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Fridell, Yih-Woei
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University of Massachusetts Medical School Worcester
Anatomy/Cell Biology
Schools of Medicine
United States
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