Review Illuminates Mitochondrial Dysfunction, Reactive Oxygen Species, and Diabetes Mellitus as a Central Pathological Axis

Diabetes mellitus (DM) is a chronic metabolic disorder that profoundly disrupts cellular homeostasis, leading to severe complications, particularly cardiovascular (CV) disease, which is the leading cause of DM-associated mortality. A critical underlying mechanism is mitochondrial dysfunction (MD), characterized by structural and functional impairments. This MD, in turn, leads to the excessive generation of reactive oxygen species (ROS), which are central mediators of oxidative stress (OS). OS is a key driver of cardiac injury and the overall progression of DM and its devastating CV sequelae, highlighting a crucial gap in understanding and targeting these interconnected pathways.

This comprehensive review synthesizes recent literature to elucidate the intricate relationship between mitochondrial dysfunction, reactive oxygen species, and diabetes mellitus. The authors systematically summarize alterations in mitochondrial dynamics, including fusion, fission, and mitophagy, alongside mtDNA damage and impaired oxidative phosphorylation. They detail specific defects such as dysregulated mitochondrial membrane potential (ΔΨm), electron transport chain (ETC) abnormalities, mitochondrial uncoupling, and substrate overload. Additionally, the review discusses various hyperglycemia-activated pathways that contribute to disease progression.

The review comprehensively outlines how mitochondrial dysfunction drives diabetes pathology through multiple mechanisms. It highlights significant alterations in mitochondrial dynamics, including impaired fusion, fission, and mitophagy, alongside widespread mtDNA damage. Impaired oxidative phosphorylation is characterized by dysregulated mitochondrial membrane potential (ΔΨm), defects in the electron transport chain (ETC), uncoupling, and substrate overload. These mitochondrial impairments lead to excessive ROS production, fueling oxidative stress. > Hyperglycemia activates several detrimental pathways, including polyol flux, advanced glycation end-product (AGE)-RAGE interactions, protein kinase C (PKC)/nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation, and poly(ADP-ribose) polymerase 1 (PARP-1)-mediated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) inhibition. These pathways collectively contribute to inflammation, endothelial dysfunction, β-cell failure, insulin resistance, and both microvascular and macrovascular injury in DM. Diagnostic strategies discussed include mtDNA analysis, bioenergetic assays, metabolomics, proteomics, and imaging techniques like PET, MRI, and NIRS.