title: Mitochondrial quality-control dysregulation in conditional HO-1-/-mice.
abstract: The heme oxygenase-1 (Hmox1; HO-1) pathway was tested for defense of mitochondrial quality control in cardiomyocyte-specificHmox1KO mice (HO-1[CM]-/-) exposed to oxidative stress (100% O2). After 48 hours of exposure, these mice showed persistent cardiac inflammation and oxidative tissue damage that caused sarcomeric disruption, cardiomyocyte death, left ventricular dysfunction, and cardiomyopathy, while control hearts showed minimal damage. After hyperoxia, HO-1(CM)-/-hearts showed suppression of the Pgc-1α/nuclear respiratory factor-1 (NRF-1) axis, swelling, low electron density mitochondria by electron microscopy (EM), increased cell death, and extensive collagen deposition. The damage mechanism involves structurally deficient autophagy/mitophagy, impaired LC3II processing, and failure to upregulatePink1- andPark2-mediated mitophagy. The mitophagy pathway was suppressed through loss of NRF-1 binding to proximal promoter sites on both genes. These results indicate that cardiacHmox1induction not only prevents heme toxicity, but also regulates the timing and registration of genetic programs for mitochondrial quality control that limit cell death, pathological remodeling, and cardiac fibrosis.
authors.affiliation: Department of Medicine.|Department of Anesthesiology.
authors.forename: Hagir B
authors.initials: HB
authors.lastname: Suliman
authors.affiliation: Department of Surgery, and.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Keenan
authors.affiliation: Department of Medicine.|Department of Anesthesiology.|Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Claude A
authors.initials: CA
authors.lastname: Piantadosi
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D051547:Heme Oxygenase-1 / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000473:pathology*; D063306:Mitophagy; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse