Waypa 2001 Circ Res

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Waypa GB, Chandel NS, Schumacker PT (2001) Model for Hypoxic Pulmonary Vasoconstriction Involving Mitochondrial Oxygen Sensing. Circ Res 88:1259–1266.

» PMID:11420302 Open Access

Waypa GB, Chandel NS, Schumacker PT (2001) Circ Res

Abstract: We tested whether mitochondria function as the O(2) sensor underlying hypoxic pulmonary vasoconstriction (HPV). In buffer-perfused rat lungs, rotenone, myxothiazol, and diphenyleneiodonium, which inhibit mitochondria in the proximal region of the electron transport chain (ETC), abolished HPV without attenuating the response to U46619. Cyanide and antimycin A inhibit electron transfer in the distal region of the ETC, but they did not abolish HPV. Cultured pulmonary artery (PA) myocytes contract in response to hypoxia or to U46619. The hypoxic response was abolished while the response to U46619 was maintained in mutant (rho(0)) PA myocytes lacking a mitochondrial ETC. To test whether reactive oxygen species (ROS) derived from mitochondria act as signaling agents in HPV, the antioxidants pyrrolidinedithiocarbamate and ebselen and the Cu,Zn superoxide dismutase inhibitor diethyldithiocarbamate were used. These abolished HPV without affecting contraction to U46619, suggesting that ROS act as second messengers. In cultured PA myocytes, oxidation of intracellular 2',7'-dichlorofluorescin diacetate (DCFH) dye increased under 2% O(2), indicating that myocytes increase their generation of H(2)O(2) during hypoxia. This was attenuated by myxothiazol, implicating mitochondria as the source of increased ROS during HPV. These results indicate that mitochondrial ATP is not required for HPV, that mitochondria function as O(2) sensors during hypoxia, and that ROS generated in the proximal region of the ETC act as second messengers in the response.

Cited by

  • Komlódi T, Sobotka O, Gnaiger E (2021) Facts and artefacts on the oxygen dependence of hydrogen peroxide production using Amplex UltraRed. Bioenerg Commun 2021.4. https://doi:10.26124/BEC:2021-0004
  • Komlódi T, Schmitt S, Zdrazilova L, Donnelly C, Zischka H, Gnaiger E (2022) Oxygen dependence of hydrogen peroxide production in isolated mitochondria and permeabilized cells. MitoFit Preprints 2022 (in prep).
  • Komlódi T, Gnaiger E (2022) Discrepancy on oxygen dependence of mitochondrial ROS production - review. MitoFit Preprints 2022 (in prep).

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MitoFit 2021 AmR, MitoFit 2021 AmR-O2, MitoFit 2022 ROS review