Abstract
Heme oxygenase-1 is induced by many cellular stressors and catalyzes the breakdown of heme to generate carbon monoxide and bilirubin, which confer cytoprotection. The role of HO-1 likely extends beyond the simple production of antioxidants, for example HO-1 activity has also been implicated in metabolism, but this function remains unclear. Here we used an HO-1 knockout lung cell line to further define the contribution of HO-1 to cellular metabolism. We found that knockout cells exhibit reduced growth and mitochondrial respiration, measured by oxygen consumption rate. Specifically, we found that HO-1 contributed to electron transport chain activity and utilization of certain mitochondrial fuels. Loss of HO-1 had no effect on intracellular non-heme iron concentration or on proteins whose levels and activities depend on available iron. We show that HO-1 supports essential functions of mitochondria, which highlights the protective effects of HO-1 in diverse pathologies and tissue types. Our results suggest that regulation of heme may be an equally significant role of HO-1.
Highlights
The clinical administration of supplemental oxygen to premature babies is sometimes necessary to support life as their lungs and alveoli are not completely developed
As HO-1 is induced in the lung and in vitro in response to hyperoxia and other stresses, we wished to better understand the role of HO-1 in these cells
We generated mouse embryonic fibroblast cells (MEFs) that were from wild-type (WT) or HO-1 global knockout (KO) mice [23], and we used these as controls for expression of HO-1
Summary
The clinical administration of supplemental oxygen to premature babies is sometimes necessary to support life as their lungs and alveoli are not completely developed. Administration of oxygen at concentrations higher than ambient (>21%) has its own negative consequences owing to the toxic effects of reactive oxygen on tissues, cells, and their subcellular building blocks. Upon oxidative damage or injury the pro-oxidant heme molecule may be released, causing further damage [1]. One defense mechanism in the lung is induction of anti-oxidant programs including increased expression and activity of heme oxygenase-1 (hmox, HO-1) [2,3]. The end products of heme catalysis include the antioxidant molecule bilirubin, the anti-inflammatory CO, and ferrous iron (Fe2+), which is sequestered by ferritin. Studies have demonstrated the protective effects of HO-1 at the organismal level, for example in acute lung injury, as well as the cellular level, by reducing damage caused by reactive oxygen species (ROS) [4,5]
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