Ndufs2, a Core Subunit of Mitochondrial Complex I, Is Essential for Acute Oxygen-Sensing and Hypoxic Pulmonary Vasoconstriction

We have demonstrated for the first time, that Ndufs2, a protein subunit of electron transport chain Complex I is required for O2 sensing in the pulmonary vasculature

Kimberly J. Dunham-Snary; Danchen Wu; Fran├žois Potus; Edward A. Sykes; Jeffrey D. Mewburn; Rebecca L. Charles; Philip Eaton; Richard A. Sultanian; Stephen L. Archer

2019

Scholarcy highlights

  • Is mimicked by the Complex I inhibitor, rotenone, the molecular identity of the O sensor is unknown
  • Mitochondria-conditioned media from normoxic lungs contained more H2O2 than mitochondria-conditioned media from chronic hypoxic lungs or kidneys and uniquely attenuated Hypoxic pulmonary vasoconstriction via a catalase-dependent mechanism
  • This study demonstrates that HPV is initiated by a decrease in production of mitochondria-derived H O, which originates primarily from electron transport chain Complex I
  • Using various microscopic and protein chemistry techniques, we identified greater expression of Ndufs in pulmonary artery smooth muscle cells versus renal artery SMC, likely contributing to the tissue specificity of HPV
  • Renal mitochondria do not modulate production of H2O2 in response to acute hypoxia, as was observed in the lung. We speculate that this difference in mitochondrial function may be epigenetic, related to the environmental conditions experienced by the mitochondria in PASMC of small pulmonary arteries, which are exposed to high alveolar O2 concentrations, versus RASMC, which experience the lower arterial Po2
  • We found that chronic hypoxia and siNdufs had similar effects with respect to Complex I activity, H2O2 levels, NADH concentrations and Kv1.5 expression in both rat and human PASMC
  • Hypoxic pulmonary vasoconstriction is a rapid, reversible, homeostatic process intrinsic to the pulmonary vasculature. In response to physiological airway hypoxia, small pulmonary arteries constrict, diverting blood away from poorly oxygenated alveoli, thereby optimizing ventilation-perfusion matching and increasing systemic oxygen delivery. In contrast, systemic arteries, such as the renal arteries, dilate during hypoxia, which serves to increase systemic O delivery. Though modulated by the endothelium, HPV is intrinsic to pulmonary artery

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