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J Am Soc Nephrol. 2016 Jul;27(7):1925-32. doi: 10.1681/ASN.2015060623. Epub 2015 Nov 25.

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

Author information

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; takaabe@med.tohoku.ac.jp.

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

PMID:
26609120
PMCID:
PMC4926982
DOI:
10.1681/ASN.2015060623
[Indexed for MEDLINE]
Free PMC Article

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