Catalase-dependent H2O2 consumption by cardiac mitochondria and redox-mediated loss in insulin signaling.

We have recently demonstrated that catalase content in mouse cardiac mitochondria is selectively elevated in response to high dietary fat, a nutritional state associated with oxidative stress and loss in insulin signaling. Catalase and various isoforms of glutathione peroxidase and peroxiredoxin each catalyze the consumption of HO Catalase, located primarily within peroxisomes and to a lesser extent mitochondria, has a low binding affinity for HO relative to glutathione peroxidase and peroxiredoxin. As such, the contribution of catalase to mitochondrial HO consumption is not well understood. In the current study, using highly purified cardiac mitochondria challenged with micromolar concentrations of HO, we found that catalase contributes significantly to mitochondrial HO consumption. In addition, catalase is solely responsible for removal of HO in nonrespiring or structurally disrupted mitochondria. Finally, in mice fed a high-fat diet, mitochondrial-derived HO is responsible for diminished insulin signaling in the heart as evidenced by reduced insulin-stimulated Akt phosphorylation. While elevated mitochondrial catalase content (∼50%) enhanced the capacity of mitochondria to consume HO in response to high dietary fat, the selective increase in catalase did not prevent HO-induced loss in cardiac insulin signaling. Taken together, our results indicate that mitochondrial catalase likely functions to preclude the formation of high levels of HO without perturbing redox-dependent signaling.