Mitophagy and Noncoding RNA Regulation in Type 2 Diabetes Mellitus: Molecular Mechanisms, Tissue-Specific Evidence and Translational Perspective

Abstract

Despite significant therapeutic advances, T2DM remains a global public health challenge that leads to multiple complications, including cardiovascular, renal, hepatic, and neurodegenerative disorders. Mitochondrial dysfunction and impaired mitophagy remain fundamental, yet incompletely understood, mechanisms driving pancreatic β-cell failure, chronic inflammation, insulin resistance and diabetic complications. Emerging evidence indicates that noncoding RNAs (including microRNAs, long noncoding RNAs, and circular RNAs) are critical regulators of mitophagy and mitochondrial quality control mechanisms across metabolically active tissues. This review comprehensively examines the interplay between mitochondrial dysfunction, mitophagy impairment, and T2DM pathophysiology. It provides an overview of recent mechanistic insights into mitophagy–noncoding RNA interactions in T2DM, emphasizing tissue-specific effects, and highlights the translational potential of mitophagy-associated proteins and regulatory ncRNAs as diagnostic biomarkers and therapeutic targets. By bridging fundamental molecular biology with translational and clinical perspectives, further it provides a comprehensive framework to guide future research, accelerate biomarker discovery, and support the development of personalized interventions aimed at reducing the growing worldwide burden of T2DM and its complications.