Heme Oxygenase-2 Localizes to Mitochondria and Regulates Hypoxic Responses in Hepatocytes

Oxidative Medicine and Cellular Longevity
Paul K WaltzBrian S Zuckerbraun

Abstract

Hypoxia occurs as a part of multiple disease states, including hemorrhagic shock. Adaptive responses occur within the cell to limit the consequences of hypoxia. This includes changes in mitochondrial respiration, stress-induced cell signaling, and gene expression that is regulated by hypoxia inducible factor-1α (HIF-1α). Heme oxygenase-2 (HO-2) has been shown to be involved in oxygen sensing in several cell types. The purpose of these experiments was to test the hypothesis that HO-2 is a critical regulator of mitochondrial oxygen consumption and reactive oxygen species (ROS) production to influence hypoxia-adaptive responses such as HIF-1α protein levels and JNK signaling. Methods and Results. In vitro studies were performed in primary mouse hepatocytes. HO-2, but not HO-1, was expressed in mitochondria at baseline. Decreased oxygen consumption and increased mitochondrial ROS production in response to hypoxia were dependent upon HO-2 expression. HO-2 expression regulated HIF-1α and JNK signaling in a mitochondrial ROS-dependent manner. Furthermore, knockdown of HO-2 led to increased organ damage, systemic inflammation, tissue hypoxia, and shock in a murine model of hemorrhage and resuscitation. Conclusion. HO-2 signaling plays ...Continue Reading

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Citations

Sep 25, 2019·European Journal of Medicinal Chemistry·Sebastiano IntagliataGiuseppe Romeo
Nov 11, 2019·Archives of Biochemistry and Biophysics·Stefan W Ryter
Aug 27, 2021·Metabolites·Alexander Myrka, Leslie Buck
Sep 15, 2021·Critical Reviews in Biochemistry and Molecular Biology·Angela S FleischhackerStephen W Ragsdale

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Methods Mentioned

BETA
ELISA
electrophoresis
electron microscopy

Software Mentioned

SigmaPlot

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