Mitochonic acid 5 binds mitochondria and ameliorates renal tubular and cardiac myocyte damage

Takehiro Suzuki, Hiroaki Yamaguchi, Motoi Kikusato, Osamu Hashizume, Satoru Nagatoishi, Akihiro Matsuo, Takeya Sato, Tai Kudo, Tetsuro Matsuhashi, Kazutaka Murayama, Yuki Ohba, Shun Watanabe, Shin Ichiro Kanno, Daichi Minaki, Daisuke Saigusa, Hiroko Shinbo, Nobuyoshi Mori, Akinori Yuri, Miyuki Yokoro, Eikan MishimaHisato Shima, Yasutoshi Akiyama, Yoichi Takeuchi, Koichi Kikuchi, Takafumi Toyohara, Chitose Suzuki, Takaharu Ichimura, Jun Ichi Anzai, Masahiro Kohzuki, Nariyasu Mano, Shigeo Kure, Teruyuki Yanagisawa, Yoshihisa Tomioka, Masaaki Toyomizu, Kohei Tsumoto, Kazuto Nakada, Joseph V. Bonventre, Sadayoshi Ito, Hitoshi Osaka, Ken Ichi Hayashi, Takaaki Abe

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1925-1932
Number of pages8
JournalJournal of the American Society of Nephrology
Volume27
Issue number7
DOIs
Publication statusPublished - 2016 Jan 1

ASJC Scopus subject areas

  • Nephrology

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    Suzuki, T., Yamaguchi, H., Kikusato, M., Hashizume, O., Nagatoishi, S., Matsuo, A., Sato, T., Kudo, T., Matsuhashi, T., Murayama, K., Ohba, Y., Watanabe, S., Kanno, S. I., Minaki, D., Saigusa, D., Shinbo, H., Mori, N., Yuri, A., Yokoro, M., ... Abe, T. (2016). Mitochonic acid 5 binds mitochondria and ameliorates renal tubular and cardiac myocyte damage. Journal of the American Society of Nephrology, 27(7), 1925-1932. https://doi.org/10.1681/ASN.2015060623