Back to Search
Start Over
Mitochonic Acid 5 Binds Mitochondria and Ameliorates Renal Tubular and Cardiac Myocyte Damage
- Source :
- Journal of the American Society of Nephrology : JASN. 27(7)
- Publication Year :
- 2015
-
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.
- Subjects :
- 0301 basic medicine
Male
Mitochondrial DNA
Mitochondrial disease
Myocytes, Smooth Muscle
Oxidative phosphorylation
Mitochondrion
Pharmacology
Kidney
medicine.disease_cause
Phenylbutyrate
Rats, Sprague-Dawley
03 medical and health sciences
Mice
Up Front Matters
medicine
Animals
Myocytes, Cardiac
chemistry.chemical_classification
Reactive oxygen species
ATP synthase
biology
Indoleacetic Acids
Chemistry
General Medicine
Acute Kidney Injury
medicine.disease
Phenylbutyrates
Mitochondria
Mice, Inbred C57BL
030104 developmental biology
Kidney Tubules
Nephrology
Reperfusion Injury
biology.protein
Brief Communications
Oxidative stress
Power Plants
Subjects
Details
- ISSN :
- 15333450
- Volume :
- 27
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Journal of the American Society of Nephrology : JASN
- Accession number :
- edsair.doi.dedup.....45fe914f54798368fe8d88d5d61aa957