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 2

Posthyperoxia oxidative stress, inflammation, and cell death after ablation of cardiac HO-1 in mice.

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Posthyperoxia oxidative stress, inflammation, and cell death after ablat...
(A) Cardiac levels of malonaldehyde, (B) cardiac level of carbonylated proteins, and (C) 8- OHdG levels in the 4 groups of mice (mean ± SEM; *P < 0.05 for pre- vs. posthyperoxia; n = 6/ group). (D–F) Inflammatory marker analysis by qPCR for IL-1β, IL-18, and iNOS (NOS2) (mean ± SEM; *P < 0.05 for pre- vs. posthyperoxia; n = 6/group). (G) TUNEL-positive cells in cardiac sections of the 4 groups of mice. Images are overlays of TUNEL-positive nuclei (red) with DAPI stained nuclei (blue). The magenta florescence indicates TUNEL positive cells. Excessive TUNEL staining is observed after tamoxifen in HO-1(CM)–/– mice after hyperoxia compared with the other groups (scale bar = 20 μm). (H) Quantitation of TUNEL positive nuclei in the heart sections (mean ± SEM; horizontal bars represent mean values.*P < 0.05 for pre- vs. posthyperoxia; n = 6/group; 2-way ANOVA).