PMID- 30520688 OWN - NLM STAT- MEDLINE DCOM- 20191226 LR - 20200930 IS - 1522-1504 (Electronic) IS - 1040-0605 (Print) IS - 1040-0605 (Linking) VI - 316 IP - 2 DP - 2019 Feb 1 TI - Impaired hypoxic pulmonary vasoconstriction in a mouse model of Leigh syndrome. PG - L391-L399 LID - 10.1152/ajplung.00419.2018 [doi] AB - Hypoxic pulmonary vasoconstriction (HPV) is a physiological vasomotor response that maintains systemic oxygenation by matching perfusion to ventilation during alveolar hypoxia. Although mitochondria appear to play an essential role in HPV, the impact of mitochondrial dysfunction on HPV remains incompletely defined. Mice lacking the mitochondrial complex I (CI) subunit Ndufs4 ( Ndufs4(-/-)) develop a fatal progressive encephalopathy and serve as a model for Leigh syndrome, the most common mitochondrial disease in children. Breathing normobaric 11% O(2) prevents neurological disease and improves survival in Ndufs4(-/-) mice. In this study, we found that either genetic Ndufs4 deficiency or pharmacological inhibition of CI using piericidin A impaired the ability of left mainstem bronchus occlusion (LMBO) to induce HPV. In mice breathing air, the partial pressure of arterial oxygen during LMBO was lower in Ndufs4(-/-) and in piericidin A-treated Ndufs4(+/+) mice than in respective controls. Impairment of HPV in Ndufs4(-/-) mice was not a result of nonspecific dysfunction of the pulmonary vascular contractile apparatus or pulmonary inflammation. In Ndufs4-deficient mice, 3 wk of breathing 11% O(2) restored HPV in response to LMBO. When compared with Ndufs4(-/-) mice breathing air, chronic hypoxia improved systemic oxygenation during LMBO. The results of this study show that, when breathing air, mice with a congenital Ndufs4 deficiency or chemically inhibited CI function have impaired HPV. Our study raises the possibility that patients with inborn errors of mitochondrial function may also have defects in HPV. FAU - Schleifer, Grigorij AU - Schleifer G AD - Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts. FAU - Marutani, Eizo AU - Marutani E AD - Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts. FAU - Ferrari, Michele AU - Ferrari M AD - Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts. FAU - Sharma, Rohit AU - Sharma R AD - Howard Hughes Medical Institute and Department of Molecular Biology, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts. FAU - Skinner, Owen AU - Skinner O AD - Howard Hughes Medical Institute and Department of Molecular Biology, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts. FAU - Goldberger, Olga AU - Goldberger O AD - Howard Hughes Medical Institute and Department of Molecular Biology, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts. FAU - Grange, Robert Matthew Henry AU - Grange RMH AD - Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts. FAU - Peneyra, Kathryn AU - Peneyra K AD - Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts. FAU - Malhotra, Rajeev AU - Malhotra R AD - Cardiology Division and Cardiovascular Research Center, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts. FAU - Wepler, Martin AU - Wepler M AD - Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts. AD - Institut fur Anasthesiologische Pathophysiologie und Verfahrensentwicklung , Ulm , Germany. FAU - Ichinose, Fumito AU - Ichinose F AD - Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts. FAU - Bloch, Donald B AU - Bloch DB AD - Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts. AD - Division of Rheumatology, Allergy and Immunology, Department of Medicine, Harvard Medical School and Massachusetts General Hospital , Boston, Massachusetts. FAU - Mootha, Vamsi K AU - Mootha VK AD - Howard Hughes Medical Institute and Department of Molecular Biology, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts. FAU - Zapol, Warren M AU - Zapol WM AD - Anesthesia Center for Critical Care Research of the Department of Anesthesia, Critical Care, and Pain Medicine, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts. LA - eng GR - K08 HL111210/HL/NHLBI NIH HHS/United States GR - R01 HL142809/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181206 PL - United States TA - Am J Physiol Lung Cell Mol Physiol JT - American journal of physiology. Lung cellular and molecular physiology JID - 100901229 RN - 0 (Ndufs4 protein, mouse) RN - EC 7.1.1.2 (Electron Transport Complex I) SB - IM MH - Animals MH - Bronchi/metabolism MH - Disease Models, Animal MH - Electron Transport Complex I/*deficiency MH - Hypoxia/metabolism/*physiopathology MH - Leigh Disease/*physiopathology MH - Lung/metabolism/physiopathology MH - Mice, Transgenic MH - Mitochondria/metabolism MH - Pulmonary Artery/metabolism MH - Pulmonary Circulation/physiology MH - Vasoconstriction/*physiology PMC - PMC6397345 OTO - NOTNLM OT - Leigh syndrome OT - complex I OT - hypoxic pulmonary vasoconstriction OT - mice OT - mitochondria COIS- V. K. Mootha and W. M. Zapol are coinventors on a patent application submitted by Massachusetts General Hospital on the use of hypoxia as a therapy. V. K. Mootha owns equity stake in Raze Therapeutics and is a paid consultant for Janssen Pharmaceutics and 5AM Ventures. EDAT- 2018/12/07 06:00 MHDA- 2019/12/27 06:00 PMCR- 2018/12/06 CRDT- 2018/12/07 06:00 PHST- 2018/12/07 06:00 [pubmed] PHST- 2019/12/27 06:00 [medline] PHST- 2018/12/07 06:00 [entrez] PHST- 2018/12/06 00:00 [pmc-release] AID - L-00419-2018 [pii] AID - 10.1152/ajplung.00419.2018 [doi] PST - ppublish SO - Am J Physiol Lung Cell Mol Physiol. 2019 Feb 1;316(2):L391-L399. doi: 10.1152/ajplung.00419.2018. Epub 2018 Dec 6.