Bypassing mitochondrial complex III using alternative oxidase inhibits acute pulmonary oxygen sensing.
Natascha SommerNasim AlebrahimdehkordiOleg PakFenja KnoeppIevgen StrielkovSusan ScheibeEric DufourAna AndjelkovićAkylbek SydykovAlireza SarajiAleksandar PetrovicKarin QuanzMatthias HeckerManish KumarJoel WahlSimone KrautWerner SeegerRalph Theo SchermulyHossein Ardeschir GhofraniKerstin RamserThomas BraunHoward T JacobsNorbert WeissmannMarten SziborPublished in: Science advances (2020)
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.
Keyphrases
- pulmonary hypertension
- liver failure
- drug induced
- respiratory failure
- aortic dissection
- oxidative stress
- endothelial cells
- pulmonary artery
- hepatitis b virus
- magnetic resonance
- hydrogen peroxide
- pulmonary arterial hypertension
- cell death
- high grade
- magnetic resonance imaging
- metabolic syndrome
- skeletal muscle
- insulin resistance
- extracorporeal membrane oxygenation