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.
-Health Relevance A decline in mitochondrial function occurs during aging, which 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 important step to limiting pathologies associated with loss of mitochondrial function. In this proposal, we aim to understand the underlying mechanisms by which a single transcription factor coordinates mitochondrial network biogenesis and recovery via independent functions in mitochondrial compartments and the nucleus. !
|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|
Showing the most recent 10 out of 12 publications