The main hypothesis to be tested in this proposal is that the mitochondrial unfolded protein response (UPRmt) is broadly relevant to cardiac ischemic injury. Mitochondria are important mediators of hypoxic damage and are targets for protective interventions. In the genetic model organism C. elegans, the UPRmt's mechanism of action has recently been described: mitochondrial proteotoxic stress regulates the matrix import and subsequent degradation of ATFS-1, a bZip transcription factor with dual targeting motifs. When matrix import is prevented, ATFS-1 traffics to the nucleus and activates a pro-survival repertoire of genes. However, excessive UPRmt activation can lead to growth arrest. The focus of this proposal is to define the relevance of the UPRmt and ATFS-1 trafficking to hypoxic susceptibility in C. elegans and mammals. Identifying the mammalian ATFS- 1 ortholog is likely to be broadly significant, since the UPRmt has relevance to a wide range of disease phenotypes and to aging itself. Finally, we intend to test several clinically useful drugs that inhibit proteasome activity for their ability to activate the UPRmt and ask whether the extent of UPRmt activation regulates its functional outcome (ie, hypoxic adaptation versus susceptibility). Importantly, this work may lead to changes in the anti-neoplastic agents used to treat cancers in patients who are at an increased risk of an ischemic event.

Public Health Relevance

Heart attack and stroke are both caused by a lack of oxygen to the cells. We have identified a novel signaling pathway in the genetic model organism C. elegans that allows the engine of the cell (the mitochondria) to communicate its status to the nucleus, where stress responses are coordinated. We intend to define the mechanism by which they protect cells against damage induced by low oxygen, to identify the mammalian protein that plays a similar role, and to determine how anti-cancer drugs affect this pathway. This may have particular clinical relevance when treating patients who are at risk for heart attack.

National Institute of Health (NIH)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Gaillard, Shawn R
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University of Rochester
Internal Medicine/Medicine
School of Medicine & Dentistry
United States
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