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

Abstract

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.

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Published Version (Please cite this version)

10.1172/jci.insight.85817

Publication Info

Hull, Travis D, Ravindra Boddu, Lingling Guo, Cornelia C Tisher, Amie M Traylor, Bindiya Patel, Reny Joseph, Sumanth D Prabhu, et al. (2017). Heme oxygenase-1 regulates mitochondrial quality control in the heart. JCI Insight, 1(2). p. e85817. 10.1172/jci.insight.85817 Retrieved from https://hdl.handle.net/10161/13987.

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Scholars@Duke

Suliman

Hagir B. Suliman

Associate Professor in Anesthesiology

Dr. Suliman is an expert in the molecular and cell biology of mammalian diseases, particularly in the molecular regulation of oxidant inflammatory responses in the heart and lung. She has a strong interest and expertise in the transcriptional control of cell metabolism, especially mitochondrial biogenesis and mitochondrial-mediated apoptosis and necrosis. Her recent publications have focused on the redox-regulation of nuclear transcription factors involved in both mitochondrial biogenesis and cellular adaptation to oxidative and nitrosative stress. Specifically, she has undertaken promoter analyses of nuclear respiratory factors-1 and -2 that indicate that these transcription factor genes are controlled by redox-regulated signaling networks activated by reactive oxygen and nitrogen species, and carbon monoxide. Dr. Suliman and her colleagues have reported that the cancer chemotherapeutic, doxorubicin, disrupts cardiac mitochondrial biogenesis through mitochondrial oxidant production, which promotes intrinsic apoptosis, while heme oxygenase-1 up-regulates adaptive mitochondrial biogenesis and opposes apoptosis through close regulation of mitochondrial ROS signaling by physiological CO production, thus forestalling fibrosis and cardiomyopathy. Most recently I have been defining the role of mitochondrial transcription factors in regulating cell survival, proliferation and differentiation including in embryonic stem cells and pluripotent cells.

Piantadosi

Claude Anthony Piantadosi

Professor Emeritus of Medicine

Dr. Piantadosi's laboratory has special expertise in the pathogenic mechanisms of acute organ failure, particularly acute lung injury (ALI), with an emphasis on the molecular regulatory roles of the physiological gases— oxygen, carbon monoxide, and nitric oxide— as they relate to the damage responses to acute inflammation. The basic science focuses on oxidative processes and redox-regulation, especially the molecular mechanisms by which reactive oxygen and nitrogen species transmit biological signals involved in the maintenance of energy metabolism and mitochondrial health, but also contribute to pathogenesis and to the resolution of tissue injury.

Clinically, ALI and the related syndrome of multiple organ failure has a high mortality, which is related to the host inflammatory response, but is not well understood scientifically; thus, the laboratory is devoted to understanding these mechanisms in the context of the host response to relevant but well-controlled experimental manipulations including hyperoxia, bacterial infections, toxic drugs, and cytokine/chemokine signals. The approach relies on animal models, mainly transgenic and knockout mice, and cell models, especially lung and heart cells to evaluate and understand the physiology, pathology, and cell and molecular biology of the injury responses, to test independent and integrated mechanisms, and to devise interventions to prevent damage.

Apart from the lung, significant work is devoted to understanding damage to the heart, brain, liver, and kidney caused by these immune mechanisms, specifically emphasizing the role of mitochondria, key targets and sources of oxidative damage. This damage compromises their ability to support energy homeostasis and advanced cellular functions, and impacts on the important roles these organelles play in cell death by apoptosis and necrosis as well as in the resolution of cellular damage and inflammation.


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