title: HtrA2/Omi influences the stability of LON protease 1 and prohibitin, proteins involved in mitochondrial homeostasis.
abstract: High temperature requirement A2 (HtrA2)/Omi is a serine protease localized in mitochondria. In response to apoptotic stimuli, HtrA2 is released to the cytoplasm and cleaves many proteins, including XIAP, Apollon/BRUCE, WT1, and Ped/Pea-15, to promote apoptosis. However, the function of HtrA2 in mitochondria under normal conditions remains unclear. Here, we show that the mitochondrial proteins, LON protease 1 (LONP1) and prohibitin (PHB), are overexpressed in HtrA2(-/-) mouse embryonic fibroblast (MEF) cells and HtrA2 knock-down HEK293T cells. We also confirm the effect of the HtrA2 protease on the stability of the above mitochondrial quality control proteins in motor neuron degeneration 2 (mnd2) mice, which have a greatly reduced protease activity as a result of a Ser276Cys missense mutation of the HtrA2 gene. In addition, PHB interacts with and is directly cleaved by HtrA2. Luminescence assays demonstrate that the intracellular ATP level is decreased in HtrA2(-/-) cells compared to HtrA2(+/+) cells. HtrA2 deficiency causes a decrease in the mitochondrial membrane potential, and reactive oxygen species (ROS) generation is greater in HtrA2(-/-) cells than in HtrA2(+/+) cells. Our results implicate that HtrA2 might be an upstream regulator of mitochondrial homeostasis.
authors.affiliation: Division of Life Sciences, Korea University, 1, 5ka, Anam-dong, Sungbuk-gu, Seoul 136-701, Republic of Korea.
authors.forename: Hui-Gwan
authors.initials: HG
authors.lastname: Goo
authors.affiliation: Department of Biomedical Sciences, Department of Medical Life Sciences, College of Medicine, the Catholic University of Korea, Seoul 137-701, Republic of Korea.
authors.forename: Hyangshuk
authors.initials: H
authors.lastname: Rhim
authors.affiliation: Division of Life Sciences, Korea University, 1, 5ka, Anam-dong, Sungbuk-gu, Seoul 136-701, Republic of Korea. Electronic address: skang@korea.ac.kr.
authors.forename: Seongman
authors.initials: S
authors.lastname: Kang
mesh_terms: D000818:Animals; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D000074923:High-Temperature Requirement A Serine Peptidase 2; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D000091402:Prohibitins; D049070:Protease La / Q000378:metabolism*; D017382:Reactive Oxygen Species; D012097:Repressor Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: D024101:Mitochondrial Proteins; C000717328:PHB protein, human; D000091402:Prohibitins; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D012697:Serine Endopeptidases; C000615914:HTRA2 protein, human; D000074923:High-Temperature Requirement A Serine Peptidase 2; C000615915:Htra2 protein, mouse; D049070:Protease La
keywords: HtrA2; Mitochondria; Mitochondrial homeostasis; Mnd2; PHB; Protein quality control