Heme oxygenase-1 regulates mitochondrial quality control in the heart.

Published

Journal Article

The cardioprotective inducible enzyme heme oxygenase-1 (HO-1) degrades prooxidant heme into equimolar quantities of carbon monoxide, biliverdin, and iron. We hypothesized that HO-1 mediates cardiac protection, at least in part, by regulating mitochondrial quality control. We treated WT and HO-1 transgenic mice with the known mitochondrial toxin, doxorubicin (DOX). Relative to WT mice, mice globally overexpressing human HO-1 were protected from DOX-induced dilated cardiomyopathy, cardiac cytoarchitectural derangement, and infiltration of CD11b+ mononuclear phagocytes. Cardiac-specific overexpression of HO-1 ameliorated DOX-mediated dilation of the sarcoplasmic reticulum as well as mitochondrial disorganization in the form of mitochondrial fragmentation and increased numbers of damaged mitochondria in autophagic vacuoles. HO-1 overexpression promotes mitochondrial biogenesis by upregulating protein expression of NRF1, PGC1α, and TFAM, which was inhibited in WT animals treated with DOX. Concomitantly, HO-1 overexpression inhibited the upregulation of the mitochondrial fission mediator Fis1 and resulted in increased expression of the fusion mediators, Mfn1 and Mfn2. It also prevented dynamic changes in the levels of key mediators of the mitophagy pathway, PINK1 and parkin. Therefore, these findings suggest that HO-1 has a novel role in protecting the heart from oxidative injury by regulating mitochondrial quality control.

Full Text

Duke Authors

Cited Authors

  • Hull, TD; Boddu, R; Guo, L; Tisher, CC; Traylor, AM; Patel, B; Joseph, R; Prabhu, SD; Suliman, HB; Piantadosi, CA; Agarwal, A; George, JF

Published Date

  • 2016

Published In

Volume / Issue

  • 1 / 2

Start / End Page

  • e85817 -

PubMed ID

  • 27110594

Pubmed Central ID

  • 27110594

International Standard Serial Number (ISSN)

  • 2379-3708

Digital Object Identifier (DOI)

  • 10.1172/jci.insight.85817

Language

  • eng

Conference Location

  • United States