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

Abstract EN

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 a role in hypoxic signaling and hemorrhagic shock.

This pathway may be able to be harnessed for therapeutic effects.