title: Oxidative post-translational modifications develop LONP1 dysfunction in pressure overload heart failure.
abstract: BACKGROUND
  Mitochondrial compromise is a fundamental contributor to heart failure. Recent studies have revealed that several surveillance systems maintain mitochondrial integrity. The present study evaluated the role of mitochondrial AAA+ protease in a mouse model of pressure overload heart failure.
  
  
  RESULTS
  The fluorescein isothiocyanate casein assay and immunoblotting for endogenous mitochondrial proteins revealed a marked reduction in ATP-dependent proteolytic activity in failing heart mitochondria. The level of reduced cysteine was decreased, and tyrosine nitration and protein carbonylation were promoted in Lon protease homolog (LONP1), the most abundant mitochondrial AAA+ protease, in heart failure. Comprehensive analysis revealed that electron transport chain protein levels were increased even with a reduction in the expression of their corresponding mRNAs in heart failure, which indicated decreased protein turnover and resulted in the accumulation of oxidative damage in the electron transport chain. The induction of mitochondria-targeted human catalase ameliorated proteolytic activity and protein homeostasis in the electron transport chain, leading to improvements in mitochondrial energetics and cardiac contractility even during the late stage of pressure overload. Moreover, the infusion of mitoTEMPO, a mitochondria-targeted superoxide dismutase mimetic, recovered oxidative modifications of LONP1 and improved mitochondrial respiration capacity and cardiac function. The in vivo small interfering RNA repression of LONP1 partially canceled the protective effects of mitochondria-targeted human catalase induction and mitoTEMPO infusion.
  
  
  CONCLUSIONS
  Oxidative post-translational modifications attenuate mitochondrial AAA+ protease activity, which is involved in impaired electron transport chain protein homeostasis, mitochondrial respiration deficiency, and left ventricular contractile dysfunction. Oxidatively inactivated proteases may be an endogenous target for mitoTEMPO treatment in pressure overload heart failure.
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (A.H., Y.O., M.A., S.K., M.U., K.F., E.-I.K., S.M.); and the Department of Cardiovascular Medicine, Meiji University of Integrative Medicine, Kyoto, Japan (E.-I.K.).
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hoshino
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (A.H., Y.O., M.A., S.K., M.U., K.F., E.-I.K., S.M.); and the Department of Cardiovascular Medicine, Meiji University of Integrative Medicine, Kyoto, Japan (E.-I.K.).
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Okawa
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (A.H., Y.O., M.A., S.K., M.U., K.F., E.-I.K., S.M.); and the Department of Cardiovascular Medicine, Meiji University of Integrative Medicine, Kyoto, Japan (E.-I.K.).
authors.forename: Makoto
authors.initials: M
authors.lastname: Ariyoshi
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (A.H., Y.O., M.A., S.K., M.U., K.F., E.-I.K., S.M.); and the Department of Cardiovascular Medicine, Meiji University of Integrative Medicine, Kyoto, Japan (E.-I.K.).
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kaimoto
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (A.H., Y.O., M.A., S.K., M.U., K.F., E.-I.K., S.M.); and the Department of Cardiovascular Medicine, Meiji University of Integrative Medicine, Kyoto, Japan (E.-I.K.).
authors.forename: Motoki
authors.initials: M
authors.lastname: Uchihashi
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (A.H., Y.O., M.A., S.K., M.U., K.F., E.-I.K., S.M.); and the Department of Cardiovascular Medicine, Meiji University of Integrative Medicine, Kyoto, Japan (E.-I.K.).
authors.forename: Kuniyoshi
authors.initials: K
authors.lastname: Fukai
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (A.H., Y.O., M.A., S.K., M.U., K.F., E.-I.K., S.M.); and the Department of Cardiovascular Medicine, Meiji University of Integrative Medicine, Kyoto, Japan (E.-I.K.).
authors.forename: Eri
authors.initials: E
authors.lastname: Iwai-Kanai
authors.affiliation: From the Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (A.H., Y.O., M.A., S.K., M.U., K.F., E.-I.K., S.M.); and the Department of Cardiovascular Medicine, Meiji University of Integrative Medicine, Kyoto, Japan (E.-I.K.). matoba@koto.kpu-m.ac.jp.
authors.forename: Satoaki
authors.initials: S
authors.lastname: Matoba
mesh_terms: D000818:Animals; D003545:Cysteine / Q000378:metabolism; D004195:Disease Models, Animal; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008929:Mitochondria, Heart / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000627:therapeutic use; D010084:Oxidation-Reduction; D010880:Piperidines / Q000627:therapeutic use; D049070:Protease La / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: C555916:MitoTEMPO; D009943:Organophosphorus Compounds; D010880:Piperidines; D012333:RNA, Messenger; D049070:Protease La; D003545:Cysteine
keywords: heart failure; mitochondria; protein processing, post-translational