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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
7R01AG047182-03
Application #
9412208
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Fridell, Yih-Woei
Project Start
2015-02-01
Project End
2020-01-31
Budget Start
2017-02-15
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
$370,791
Indirect Cost
$149,423
Name
University of Massachusetts Medical School Worcester
Department
Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Haroon, Suraiya; Li, Annie; Weinert, Jaye L et al. (2018) Multiple Molecular Mechanisms Rescue mtDNA Disease in C. elegans. Cell Rep 22:3115-3125
Shpilka, Tomer; Haynes, Cole M (2018) The mitochondrial UPR: mechanisms, physiological functions and implications in ageing. Nat Rev Mol Cell Biol 19:109-120
Kumar, Anil; Katz, Liora S; Schulz, Anna M et al. (2018) Activation of Nrf2 Is Required for Normal and ChREBP?-Augmented Glucose-Stimulated ?-Cell Proliferation. Diabetes 67:1561-1575
Qureshi, Mohammed A; Haynes, Cole M; Pellegrino, Mark W (2017) The mitochondrial unfolded protein response: Signaling from the powerhouse. J Biol Chem 292:13500-13506
Fiorese, Christopher J; Haynes, Cole M (2017) Integrating the UPRmt into the mitochondrial maintenance network. Crit Rev Biochem Mol Biol 52:304-313
Deng, Pan; Haynes, Cole M (2017) Mitochondrial dysfunction in cancer: Potential roles of ATF5 and the mitochondrial UPR. Semin Cancer Biol 47:43-49
Lin, Yi-Fan; Schulz, Anna M; Pellegrino, Mark W et al. (2016) Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial unfolded protein response. Nature 533:416-9
Lin, Yi-Fan; Haynes, Cole M (2016) Metabolism and the UPR(mt). Mol Cell 61:677-682
Lamech, Lilian T; Haynes, Cole M (2015) The unpredictability of prolonged activation of stress response pathways. J Cell Biol 209:781-7
Pellegrino, Mark W; Haynes, Cole M (2015) Mitophagy and the mitochondrial unfolded protein response in neurodegeneration and bacterial infection. BMC Biol 13:22

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