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Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing.

Science advances (2020-05-20)
Natascha Sommer, Nasim Alebrahimdehkordi, Oleg Pak, Fenja Knoepp, Ievgen Strielkov, Susan Scheibe, Eric Dufour, Ana Andjelković, Akylbek Sydykov, Alireza Saraji, Aleksandar Petrovic, Karin Quanz, Matthias Hecker, Manish Kumar, Joel Wahl, Simone Kraut, Werner Seeger, Ralph T Schermuly, Hossein A Ghofrani, Kerstin Ramser, Thomas Braun, Howard T Jacobs, Norbert Weissmann, Marten Szibor
ABSTRACT

Mitochondria play an important role in sensing both acute and chronic hypoxia in the pulmonary vasculature, but their primary oxygen-sensing mechanism and contribution to stabilization of the hypoxia-inducible factor (HIF) remains elusive. Alteration of the mitochondrial electron flux and increased superoxide release from complex III has been proposed as an essential trigger for hypoxic pulmonary vasoconstriction (HPV). We used mice expressing a tunicate alternative oxidase, AOX, which maintains electron flux when respiratory complexes III and/or IV are inhibited. Respiratory restoration by AOX prevented acute HPV and hypoxic responses of pulmonary arterial smooth muscle cells (PASMC), acute hypoxia-induced redox changes of NADH and cytochrome c, and superoxide production. In contrast, AOX did not affect the development of chronic hypoxia-induced pulmonary hypertension and HIF-1α stabilization. These results indicate that distal inhibition of the mitochondrial electron transport chain in PASMC is an essential initial step for acute but not chronic oxygen sensing.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Adenosine 5′-triphosphate 镁盐, ≥95%, bacterial
Roche
细胞增殖试ELISA, BrdU(比色法), sufficient for ≤1,000 tests
Sigma-Aldrich
乙二醇-双(2-氨基乙醚)-N,N,N′,N′-四乙酸, BioUltra, for molecular biology, ≥99.0% (T)
Sigma-Aldrich
JC-1, solid
Sigma-Aldrich
L -天冬氨酸 钾盐, ≥98% (HPLC)