Mitochondrial bioenergetics dysfunction in T2DM: linking oxidative stress to insulin resistance

Insulin resistance (IR) is a core pathological feature of type 2 diabetes mellitus (T2DM) and is closely associated with mitochondrial dysfunction(definition) in insulin-sensitive tissues, including skeletal muscle, liver, and adipose tissue. Mitochondrial abnormalities-such as impaired oxidative phosphorylation (OXPHOS), dysregulated tricarboxylic acid (TCA) cycle, excessive reactive oxygen species (ROS) production, and altered mitochondrial dynamics-can contribute to IR by oxidatively modifying insulin-signaling proteins and activating inflammatory pathways (JNK/NF-κB). Recent work also implicates microRNAs (miRNAs) as modulators that link mitochondrial function and redox balance to insulin action; however, their magnitude and tissue specificity in human T2DM remain to be defined. Therapeutic strategies that target mitochondrial bioenergetics and redox homeostasis show promise, while miRNA-directed approaches are emerging. This review provides an explanatory synthesis aimed at distinguishing associations within the mitochondria-ROS-insulin resistance axis supported by solid evidence from findings influenced by specific contexts, and outlines translational opportunities and their associated delivery bottlenecks.