Catecholamine Metabolism via Monoamine Oxidase Disrupts Oxidative Phosphorylation Efficiency in Glutathione Peroxidase-4 Deficient Mouse and Human Myocardium

Glutathione peroxidase-4 (GPx4) is a selenoenzyme expressed in mitochondria and nuclear compartments which exclusively neutralizes lipid peroxides. Monoamine oxidase (MAO), an outer mitochondrial membrane-bound enzyme responsible for catecholamine metabolism, produces a reactive catechol-aldehyde and H 2 O 2 upon substrate deamination. Current findings in human myocardial samples from our lab show that obese/diabetic patients exhibit greater maximal MAO activity and content, but lower GPx4 compared with nondiabetic patients, suggesting that both increased MAO and decreased GPx4 act to compound levels of reactive aldehyde species in diabetic myocardium. Our preliminary experiments using nitro blue tetrazolium staining have revealed protein modification by catechol-aldehydes derived from norepinephrine (NE) and dopamine (DA) in whole heart lysate and isolated cardiac mitochondria from mice and humans, an effect mitigated by MAO inhibitors. We further examined the effects of catecholamine metabolism via MAO on ATP production and O 2 consumption (OxPhos) in isolated cardiac mitochondria prepared from WT and GPx4-deficient (GPx4 +/- ) mice, and in permeabilized myofibers prepared from human atrial myocardium. Both DA and NE significantly decreased ATP production and O 2 consumption in GPx4 +/- mice, but not WT, by 15% and 13%, respectively (p +/- mice. In human atrial myocardium (n=11), NE significantly decreased ATP/O by ~35% (p