Mitochondrial peptide MOTS‐c suppresses systemic and cardiac inflammasome activation in a diabetic rat model

Abstract

Type 2 diabetes mellitus (T2DM) is associated with chronic systemic and cardiac inflammation, contributing to the development of diabetic cardiomyopathy. The mitochondrial‐derived peptide mitochondrial open reading frame of the 12S rRNA type‐C (MOTS‐c) has emerged as a promising regulator of metabolic and inflammatory pathways. In this study, we investigated the effects of MOTS‐c treatment on leucine‐rich repeat and pyrin domain‐containing receptor 3 (NLRP3) inflammasome activity in a high‐fat diet and streptozotocin‐induced T2DM rat model. MOTS‐c treatment significantly reduced fasting blood glucose and circulating C‐reactive protein levels, while selectively modulating plasma inflammatory cytokines, including interleukin (IL)‐10 and IL‐1β. Immunohistochemical analysis revealed reduced levels of NLRP3, apoptosis‐associated speck‐like protein containing a caspase activation and recruitment domain (ASC), and cleaved caspase‐1 in left ventricular tissue following MOTS‐c administration. Correlation analyses linked IL‐18 and IL‐1β with elevated markers, including low‐density lipoprotein and uric acid, suggesting interplay between overall health and inflammasome activity. These results indicate that MOTS‐c modulates both systemic and cardiac inflammation in T2DM, providing a novel therapeutic approach for reducing cardiovascular risk in diabetic patients.