title: Mitochondrial Proteostatic Collapse Leads to Hypoxic Injury.
abstract: Hypoxic injury is a key pathological event in a variety of diseases. Despite the clinical importance of hypoxia, modulation of hypoxic injury mechanisms for therapeutic benefit has not been achieved, suggesting that critical features of hypoxic injury have not been identified or fully understood. Because mitochondria are the main respiratory organelles of the cell, they have been the focus of much research into hypoxic injury. Previous research has focused on mitochondria as effectors of hypoxic injury, primarily in the context of apoptosis activation and calcium regulation; however, little is known about how mitochondria themselves are injured by hypoxia. Maintenance of protein folding is essential for normal mitochondrial function, whereas failure to maintain protein homeostasis (proteostasis) appears to be a component of aging and a variety of diseases. Previously, it has been demonstrated that mitochondria possess their own unfolded protein response that is activated in response to mitochondrial protein folding stress, a response that is best understood in C. elegans. Because hypoxia has been shown to disrupt ATP production and translation of nuclear encoded proteins--both of which are shown to disrupt mitochondrial proteostasis in other contexts-we hypothesized that failure to maintain mitochondrial proteostasis may play a role in hypoxic injury. Utilizing C. elegans models of global, focal, and cell non-autonomous hypoxic injury, we have found evidence of mitochondrial protein misfolding post-hypoxia and have found that manipulation of the mitochondrial protein folding environment is an effective hypoxia protective strategy.
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, 850 Republican Street, N110, Seattle, WA 98109, USA; Medical Scientist Training Program, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Kaufman
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Washington School of Medicine, 850 Republican Street, N110, Seattle, WA 98109, USA; Department of Genome Sciences, University of Washington School of Medicine, 850 Republican Street, N110, Seattle, WA 98109, USA. Electronic address: cmc53@uw.edu.
authors.forename: C Michael
authors.initials: CM
authors.lastname: Crowder
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000502:physiology*; D004195:Disease Models, Animal; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D017510:Protein Folding; D056811:Unfolded Protein Response