15 February 2020 by Natascha Sommer

Mitochondrial alternative oxidase inhibits acute, but not chronic hypoxic signaling of the pulmonary vasculature

Background: Acute alveolar hypoxia results in hypoxic pulmonary vasoconstriction (HPV), while chronic hypoxic exposure leads to pulmonary hypertension (PH). We have recently shown that mitochondrial ROS release triggers HPV, but not PH, via a mechanism depending on mitochondrial complex IV subunit composition. We now aimed to investigate if inhibition of mitochondrial respiration and subsequent accumulation of electrons distal of complex IV may act as trigger mechanism for acute hypoxia-induced ROS release and HPV.

Methods: We used mice expressing an alternative oxidase (AOX) which can pass electrons directly from complex I or II to oxygen, when either complex III or IV is inhibited thereby avoiding electron accumulation distal from complex IV. HPV was investigated in isolated lungs, and PH in mice exposed to 4 weeks of hypoxia. Superoxide levels of isolated pulmonary arterial smooth muscle cells (PASMC) were measured by electron spin resonancespectroscopy, cellular redox state by RAMAN spectroscopy and cellular membrane potential (as cellular HPV equivalent) by patch clamp.

Results: Bypassing complex III/IV and maintaining electron flow through complex I/II by AOX expression, inhibited acute hypoxia-induced increase of NADH/NAD and superoxide levels, cellular membrane depolarization of PASMC and HPV in isolated lungs, whilst the response to a hypoxia-independent vasoconstrictive stimuli was preserved. In contrast, chronic hypoxia-induced PH in mice, and stabilization of the hypoxia-inducible factor 1α in PASMC were not affected by AOX expression.

Conclusion: These results confirm our previous observation that mitochondrial ROS release is essential for acute, but not chronic hypoxic signaling in the pulmonary vasculature. Inhibition of mitochondrial respiration resulting in electron accumulation at complex I/III may act as initial trigger for hypoxia-induced superoxide release and HPV.

Key Contributors

Sommer N, Alebrahimdehkordi N, Pak O, Knoepp F, Scheibe S, Sydykov A, Saraji A, Simone Kraut, Matthias Hecker, Quanz K, Joel Wahl, Seeger W, Ghofrani HA, Schermuly RT, Grimminger F, Kerstin Ramser, Braun T, Jacobs HT, Weissmann N, Szibor M Excellence Cluster Cardio-Pulmonary Institute (CPI), University of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig-University, Giessen, D-35392 Giessen, Germany. Department of Engineering Sciences and Mathematics, Luleå University of Technology, SE-97187 Luleå, Sweden. BioMediTech & Tampere University Hospital, Faculty of Medicine and Health Technology, Tampere University, FI-33520 Tampere, Finland. Department I, Cardiac Development and Remodelling, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany.

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