ORIGINAL RESEARCH article
Front. Physiol.
Sec. Mitochondrial Research
Volume 16 - 2025 | doi: 10.3389/fphys.2025.1602271
Mitochondria-derived peptide MOTS-c restores mitochondrial respiration in type 2 diabetic heart
Provisionally accepted
- 1Auckland Bioengineering Institute, Faculty of Engineering, University of Auckland, Auckland, New Zealand
- 2Department of Engineering Science and Biomedical Engineering, Faculty of Engineering, University of Auckland, Auckland, Auckland, New Zealand
- 3School of Biological Sciences, Faculty of Science, The University of Auckland, Auckland, Auckland, New Zealand
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Type 2 diabetes (T2D) is a global epidemic, and heart failure is the primary cause of premature death among T2D patients. Mitochondrial dysfunction has been linked to decreased contractile performance in diabetic heart, partly due to a disturbance in the mitochondrial capacity to supply adequate metabolic energy to contractile proteins. MOTSc, a newly discovered mitochondrial-derived peptide, has shown promise as a therapeutic for restoring energy homeostasis and muscle function in metabolic diseases. However, whether MOTS-c therapy improves T2D heart function by increasing mitochondrial bioenergetic function remains unknown. Here we studied the mitochondrial bioenergetic function of heart tissues isolated from a rat model mimicking type 2 diabetes induced by a high-fat diet and low-dose streptozotocin. Treated diabetic group received MOTS-c (15 mg/kg) daily injection for three weeks. We employed high-resolution respirometric and fluorometric techniques to simultaneously assess mitochondrial ATP production and hydrolysis capacity, reactive oxygen species (ROS) production, and oxygen flux in cardiac tissue homogenates. We found that untreated T2D rats had hyperglycemia, poor glucose control, and left ventricular hypertrophy relative to controls. T2D mitochondria showed decreased oxygen flux at the oxidative phosphorylation (OXP) while ROS production, ATP production and hydrolysis rates remained unchanged. Diabetic rats treated with MOTS-c showed decreased fasting glucose levels, improved glucose homeostasis, and decreased degree of cardiac hypertrophy. At the subcellular level, MOTS-c treated mitochondria showed increased OXPHOS respiration and ROS levels and decreased ATP hydrolysis rate during anoxic conditions. These findings demonstrate beneficial effects of MOTS-c treatment on glucose homeostasis and suggest a useful therapeutic option for diabeticrelated cardiomyopathy and mitochondrial dysfunction.
Keywords: MOTS-c, Diabetic heart, mitochondrial respiration, ATP, Reactive Oxygen Species
Received: 29 Mar 2025; Accepted: 02 Jun 2025.
Copyright: © 2025 Pham, Taberner, Hickey and Han. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Toan Pham, Auckland Bioengineering Institute, Faculty of Engineering, University of Auckland, Auckland, New Zealand
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