title: Mitochonic Acid 5 Binds Mitochondria and Ameliorates Renal Tubular and Cardiac Myocyte Damage.
abstract: Mitochondrial dysfunction causes increased oxidative stress and depletion of ATP, which are involved in the etiology of a variety of renal diseases, such as CKD, AKI, and steroid-resistant nephrotic syndrome. Antioxidant therapies are being investigated, but clinical outcomes have yet to be determined. Recently, we reported that a newly synthesized indole derivative, mitochonic acid 5 (MA-5), increases cellular ATP level and survival of fibroblasts from patients with mitochondrial disease. MA-5 modulates mitochondrial ATP synthesis independently of oxidative phosphorylation and the electron transport chain. Here, we further investigated the mechanism of action for MA-5. Administration of MA-5 to an ischemia-reperfusion injury model and a cisplatin-induced nephropathy model improved renal function. In in vitro bioenergetic studies, MA-5 facilitated ATP production and reduced the level of mitochondrial reactive oxygen species (ROS) without affecting activity of mitochondrial complexes I-IV. Additional assays revealed that MA-5 targets the mitochondrial protein mitofilin at the crista junction of the inner membrane. In Hep3B cells, overexpression of mitofilin increased the basal ATP level, and treatment with MA-5 amplified this effect. In a unique mitochondrial disease model (Mitomice with mitochondrial DNA deletion that mimics typical human mitochondrial disease phenotype), MA-5 improved the reduced cardiac and renal mitochondrial respiration and seemed to prolong survival, although statistical analysis of survival times could not be conducted. These results suggest that MA-5 functions in a manner differing from that of antioxidant therapy and could be a novel therapeutic drug for the treatment of cardiac and renal diseases associated with mitochondrial dysfunction.
authors.affiliation: Divisions of Nephrology, Endocrinology, and Vascular Medicine and Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Takehiro
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan;
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamaguchi
authors.affiliation: Animal Nutrition, Life Sciences, Graduate School of Agricultural Science.
authors.forename: Motoi
authors.initials: M
authors.lastname: Kikusato
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan;
authors.forename: Osamu
authors.initials: O
authors.lastname: Hashizume
authors.affiliation: Department of Bioengineering, University of Tokyo, Tokyo, Japan;
authors.forename: Satoru
authors.initials: S
authors.lastname: Nagatoishi
authors.affiliation: Divisions of Nephrology, Endocrinology, and Vascular Medicine and.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsuo
authors.affiliation: Departments of Molecular Pharmacology.
authors.forename: Takeya
authors.initials: T
authors.lastname: Sato
authors.affiliation: Primetech Co. Ltd., Tokyo, Japan;
authors.forename: Tai
authors.initials: T
authors.lastname: Kudo
authors.affiliation: Pediatrics and.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Matsuhashi
authors.affiliation: Division of Biomedical Measurements and Diagnostics and.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Murayama
authors.affiliation: Divisions of Nephrology, Endocrinology, and Vascular Medicine and.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ohba
authors.affiliation: Divisions of Nephrology, Endocrinology, and Vascular Medicine and.
authors.forename: Shun
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Division of Dynamic Proteome in Cancer and Aging, Institute of Development, Aging and Cancer.
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Kanno
authors.affiliation: Graduate School of Pharmaceutical Sciences, and.
authors.forename: Daichi
authors.initials: D
authors.lastname: Minaki
authors.affiliation: Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan;
authors.forename: Daisuke
authors.initials: D
authors.lastname: Saigusa
authors.affiliation: Kanagawa Children's Medical Center, Yokohama, Japan;
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shinbo
authors.affiliation: Internal Medicine and Rehabilitation Science, and.
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Mori
authors.affiliation: Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan;
authors.forename: Akinori
authors.initials: A
authors.lastname: Yuri
authors.affiliation: Department of Food Sciences and Nutrition, School of Human Environmental Sciences, Mukogawa Women's University, Nishinomiya, Japan;
authors.forename: Miyuki
authors.initials: M
authors.lastname: Yokoro
authors.affiliation: Divisions of Nephrology, Endocrinology, and Vascular Medicine and.
authors.forename: Eikan
authors.initials: E
authors.lastname: Mishima
authors.affiliation: Divisions of Nephrology, Endocrinology, and Vascular Medicine and.
authors.forename: Hisato
authors.initials: H
authors.lastname: Shima
authors.affiliation: Divisions of Nephrology, Endocrinology, and Vascular Medicine and.
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Akiyama
authors.affiliation: Divisions of Nephrology, Endocrinology, and Vascular Medicine and.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Takeuchi
authors.affiliation: Divisions of Nephrology, Endocrinology, and Vascular Medicine and Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, Japan;
authors.forename: Koichi
authors.initials: K
authors.lastname: Kikuchi
authors.affiliation: Divisions of Nephrology, Endocrinology, and Vascular Medicine and.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Toyohara
authors.affiliation: Divisions of Nephrology, Endocrinology, and Vascular Medicine and.
authors.forename: Chitose
authors.initials: C
authors.lastname: Suzuki
authors.affiliation: Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Takaharu
authors.initials: T
authors.lastname: Ichimura
authors.affiliation: Graduate School of Pharmaceutical Sciences, and.
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Anzai
authors.affiliation: Internal Medicine and Rehabilitation Science, and.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kohzuki
authors.affiliation: Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan;
authors.forename: Nariyasu
authors.initials: N
authors.lastname: Mano
authors.affiliation: Pediatrics and.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.affiliation: Departments of Molecular Pharmacology.
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Yanagisawa
authors.affiliation: Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan;
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Tomioka
authors.affiliation: Animal Nutrition, Life Sciences, Graduate School of Agricultural Science.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toyomizu
authors.affiliation: Department of Bioengineering, University of Tokyo, Tokyo, Japan;
authors.forename: Kohei
authors.initials: K
authors.lastname: Tsumoto
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan;
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nakada
authors.affiliation: Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts;
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Bonventre
authors.affiliation: Divisions of Nephrology, Endocrinology, and Vascular Medicine and.
authors.forename: Sadayoshi
authors.initials: S
authors.lastname: Ito
authors.affiliation: Division of Pediatrics, Jichi Medical University, Tochigi, Japan; and.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.affiliation: Department of Biochemistry, Okayama University of Science, Okayama, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Divisions of Nephrology, Endocrinology, and Vascular Medicine and Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, Japan; Department of Medical Science, Tohoku University Graduate School of Biomedical Engineering, Sendai, Japan; takaabe@med.tohoku.ac.jp.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Abe
mesh_terms: D000818:Animals; D007210:Indoleacetic Acids / Q000494:pharmacology*; D007684:Kidney Tubules / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D010654:Phenylbutyrates / Q000494:pharmacology*
chemical_list: C000605791:4-(2,4-difluorophenyl)-2-(1H-indol-3-yl)-4-oxobutanoic acid; D007210:Indoleacetic Acids; D010654:Phenylbutyrates
keywords: acute renal failure; cardiovascular disease; chronic kidney disease; ischemia-reperfusion; mitochondria; nephrotic syndrome