Pham Toan, Taberner Andrew, Hickey Anthony, Han June-Chiew
Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand.
Department of Engineering Science and Biomedical Engineering, The University of Auckland, Auckland, New Zealand.
Front Physiol. 2025 Jun 30;16:1602271. doi: 10.3389/fphys.2025.1602271. eCollection 2025.
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. MOTS-c, 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 3 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 diabetic-related cardiomyopathy and mitochondrial dysfunction.
2型糖尿病(T2D)是一种全球性流行病,心力衰竭是T2D患者过早死亡的主要原因。线粒体功能障碍与糖尿病心脏收缩功能下降有关,部分原因是线粒体向收缩蛋白提供足够代谢能量的能力受到干扰。MOTS-c是一种新发现的线粒体衍生肽,已显示出有望成为恢复代谢疾病中能量稳态和肌肉功能的治疗方法。然而,MOTS-c疗法是否通过增加线粒体生物能量功能来改善T2D心脏功能仍不清楚。
在这里,我们研究了从模拟高脂饮食和低剂量链脲佐菌素诱导的2型糖尿病大鼠模型中分离的心脏组织的线粒体生物能量功能。治疗的糖尿病组每天注射MOTS-c(15mg/kg),持续3周。我们采用高分辨率呼吸测定法和荧光测定技术同时评估心脏组织匀浆中的线粒体ATP产生和水解能力、活性氧(ROS)产生和氧通量。
我们发现,与对照组相比,未经治疗的T2D大鼠患有高血糖、血糖控制不佳和左心室肥厚。T2D线粒体在氧化磷酸化(OXP)时氧通量降低,而ROS产生、ATP产生和水解速率保持不变。用MOTS-c治疗的糖尿病大鼠空腹血糖水平降低,血糖稳态改善,心脏肥厚程度降低。在亚细胞水平上,用MOTS-c治疗的线粒体在缺氧条件下显示出氧化磷酸化呼吸增加、ROS水平增加和ATP水解速率降低。
这些发现证明了MOTS-c治疗对血糖稳态的有益作用,并为糖尿病相关心肌病和线粒体功能障碍提供了一种有用的治疗选择。