Mitochondrial quality-control dysregulation in conditional HO-1–/– mice
Hagir B. Suliman, … , Jeffrey E. Keenan, Claude A. Piantadosi
Hagir B. Suliman, … , Jeffrey E. Keenan, Claude A. Piantadosi
Published February 9, 2017
Citation Information: JCI Insight. 2017;2(3):e89676. https://doi.org/10.1172/jci.insight.89676.
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Research Article Inflammation Metabolism

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-specific Hmox1 KO 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 upregulate Pink1- and Park2-mediated mitophagy. The mitophagy pathway was suppressed through loss of NRF-1 binding to proximal promoter sites on both genes. These results indicate that cardiac Hmox1 induction 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

Hagir B. Suliman, Jeffrey E. Keenan, Claude A. Piantadosi

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Figure 4

HO-1 and regulation of cardiac mitochondrial biogenesis.

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HO-1 and regulation of cardiac mitochondrial biogenesis. (A) Deletion of...
(A) Deletion of HO-1 decreases cardiac mRNA expression of mitochondrial-encoded gene ND1. (B) Deletion of HO-1 decreases cardiac mRNA expression of nuclear-encoded gene ND5. (C) Mitochondrial mtDNA copy number by qPCR shows significant decline in mtDNA copies after hyperoxia in HO-1–deficient hearts. (D) Representative Western blots for nuclear-encoded NRF-1 and PGC-1α proteins that regulate the mitochondrial genome. (E and F) The quantification of NRF-1 and PGC-1α is, by densitometry, relative to loading control Lamin B. HO-1 ablation led to decreases in NRF-1 transcription factor and PGC-1α coactivator protein expression in the heart (mean ± SEM; horizontal bars represent mean values.*P < 0.05 for pre- vs. posthyperoxia; n = 6/group; 2-way ANOVA).