title: Co-regulation of mitochondrial respiration by proline dehydrogenase/oxidase and succinate.
abstract: Proline dehydrogenase/oxidase (PRODH/POX) is a mitochondrial protein critical to multiple stress pathways. Because of the roles of PRODH/POX in signaling, and its shared localization to the mitochondrial inner membrane with the electron transport chain (ETC), we investigated whether there was a direct relationship between PRODH/POX and regulation of the ETC. We found that PRODH/POX binds directly to CoQ1 and that CoQ1-dependent PRODH/POX activity required functional Complex III and Complex IV. PRODH/POX supported respiration in living cells during nutrient stress; however, expression of PRODH/POX resulted in an overall decrease in respiratory fitness. Effects on respiratory fitness were inhibited by DHP and NAC, indicating that these effects were mediated by PRODH/POX-dependent reactive oxygen species (ROS) generation. PRODH/POX expression resulted in a dose-dependent down-regulation of Complexes I-IV of the ETC, and this effect was also mitigated by the addition of DHP and NAC. We found that succinate was an uncompetitive inhibitor of PRODH/POX activity, inhibited ROS generation by PRODH/POX, and alleviated PRODH/POX effects on respiratory fitness. The findings demonstrate novel cross-talk between proline and succinate respiration in vivo and provide mechanistic insights into observations from previous animal studies. Our results suggest a potential regulatory loop between PRODH/POX and succinate in regulation of mitochondrial respiration.
authors.affiliation: Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, NCI-Frederick, 1050 Boyles Street, Bldg. 538, Rm. 144, Frederick, MD, 21702-1201, USA. chad.hancock@nih.gov.
authors.forename: Chad N
authors.initials: CN
authors.lastname: Hancock
authors.affiliation: Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, NCI-Frederick, 1050 Boyles Street, Bldg. 538, Rm. 144, Frederick, MD, 21702-1201, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Data Management Services, National Cancer Institute at Frederick, Frederick, MD, 21702, USA.
authors.forename: W Gregory
authors.initials: WG
authors.lastname: Alvord
authors.affiliation: Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, NCI-Frederick, 1050 Boyles Street, Bldg. 538, Rm. 144, Frederick, MD, 21702-1201, USA. phangj@mail.nih.gov.
authors.forename: James M
authors.initials: JM
authors.lastname: Phang
mesh_terms: D000818:Animals; D019069:Cell Respiration; D004579:Electron Transport; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism*; D011394:Proline Oxidase / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D019802:Succinic Acid / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D019802:Succinic Acid; D011394:Proline Oxidase
keywords: Energetics; Reactive oxygen species; Redox; Respiration; Signaling