Mitochonic Acid 5 Binds Mitochondria and Ameliorates Renal Tubular and Cardiac Myocyte Damage

  • J Am Soc Nephrol. 2016 Jul;27(7):1925-32. doi: 10.1681/ASN.2015060623.
Takehiro Suzuki  1 ,  Hiroaki Yamaguchi  2 ,  Motoi Kikusato  3 ,  Osamu Hashizume  4 ,  Satoru Nagatoishi  5 ,  Akihiro Matsuo  6 ,  Takeya Sato  7 ,  Tai Kudo  8 ,  Tetsuro Matsuhashi  9 ,  Kazutaka Murayama  10 ,  Yuki Ohba  6 ,  Shun Watanabe  6 ,  Shin-Ichiro Kanno  11 ,  Daichi Minaki  12 ,  Daisuke Saigusa  13 ,  Hiroko Shinbo  14 ,  Nobuyoshi Mori  15 ,  Akinori Yuri  16 ,  Miyuki Yokoro  17 ,  Eikan Mishima  6 ,  Hisato Shima  6 ,  Yasutoshi Akiyama  6 ,  Yoichi Takeuchi  6 ,  Koichi Kikuchi  18 ,  Takafumi Toyohara  6 ,  Chitose Suzuki  6 ,  Takaharu Ichimura  19 ,  Jun-Ichi Anzai  12 ,  Masahiro Kohzuki  15 ,  Nariyasu Mano  2 ,  Shigeo Kure  9 ,  Teruyuki Yanagisawa  7 ,  Yoshihisa Tomioka  16 ,  Masaaki Toyomizu  3 ,  Kohei Tsumoto  5 ,  Kazuto Nakada  4 ,  Joseph V Bonventre  19 ,  Sadayoshi Ito  6 ,  Hitoshi Osaka  20 ,  Ken-Ichi Hayashi  21 ,  Takaaki Abe  22
Affiliations
  • 1. Divisions of Nephrology, Endocrinology, and Vascular Medicine and Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts;
  • 2. Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan;
  • 3. Animal Nutrition, Life Sciences, Graduate School of Agricultural Science.
  • 4. Faculty of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan;
  • 5. Department of Bioengineering, University of Tokyo, Tokyo, Japan;
  • 6. Divisions of Nephrology, Endocrinology, and Vascular Medicine and.
  • 7. Departments of Molecular Pharmacology.
  • 8. Primetech Co. Ltd., Tokyo, Japan;
  • 9. Pediatrics and.
  • 10. Division of Biomedical Measurements and Diagnostics and.
  • 11. Division of Dynamic Proteome in Cancer and Aging, Institute of Development, Aging and Cancer.
  • 12. Graduate School of Pharmaceutical Sciences, and.
  • 13. Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan;
  • 14. Kanagawa Children's Medical Center, Yokohama, Japan;
  • 15. Internal Medicine and Rehabilitation Science, and.
  • 16. Laboratory of Oncology, Pharmacy Practice and Sciences, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai, Japan;
  • 17. Department of Food Sciences and Nutrition, School of Human Environmental Sciences, Mukogawa Women's University, Nishinomiya, Japan;
  • 18. Divisions of Nephrology, Endocrinology, and Vascular Medicine and Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, Japan;
  • 19. Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts;
  • 20. Division of Pediatrics, Jichi Medical University, Tochigi, Japan; and.
  • 21. Department of Biochemistry, Okayama University of Science, Okayama, Japan.
  • 22. 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; [email protected].
PMID: 26609120 DOI: 10.1681/ASN.2015060623
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.

Keywords
acute renal failure; cardiovascular disease; chronic kidney disease; ischemia-reperfusion; mitochondria; nephrotic syndrome.
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