Abstract

Mitochondrial dysfunction has emerged as a central mechanism linking metabolic derangements, immune 
dysregulation, and multi-organ toxicity in Type 2 Diabetes Mellitus (T2DM). Beyond its classical features of 
insulin resistance and hyperglycaemia, T2DM is characterized by impaired mitochondrial oxidative 
phosphorylation, altered mitochondrial dynamics, defective mitophagy, and excessive reactive oxygen species 
(ROS) production. These disturbances compromise cellular energy homeostasis and propagate oxidative stress, 
triggering inflammatory pathways and the release of mitochondrial damage-associated molecular patterns 
(DAMPs), which impair immune cell function. Dysfunctional mitochondria in metabolic tissues like skeletal 
muscle, liver, pancreas, and adipose tissue contribute directly to insulin resistance and β-cell failure, while in 
immune cells, they reduce regenerative capacity, promote apoptosis, and impair pathogen responses. Organ-specific 
consequences include hepatic steatosis, diabetic nephropathy, cardiomyopathy, skeletal muscle dysfunction, and 
cognitive decline. Additionally, extracellular vesicle-mediated transfer of dysfunctional mitochondria may amplify 
systemic inflammation and multi-organ stress. Therapeutic strategies targeting mitochondrial health, including 
mitochondria-specific antioxidants, modulators of mitochondrial dynamics, and enhancers of mitophagy and 
biogenesis, hold promise for mitigating both metabolic and immune dysfunction. Understanding mitochondrial 
impairment as a unifying mechanism in T2DM provides a framework for integrative interventions aimed at 
improving energy metabolism, immune competence, and organ resilience, potentially reducing disease progression 
and complications.