Mitochondrial dysfunction in diabetic neuropathy: a core pathogenic hub and therapeutic implications.

backgroundDiabetic neuropathy is a heterogeneous complication of diabetes in which sensory loss, neuropathic pain, autonomic dysfunction and distal axonal degeneration cannot be fully explained by hyperglycaemia alone. Because peripheral axons, Schwann cells and autonomic neurons depend on sustained bioenergetic support, mitochondrial injury has emerged as a central link between metabolic overload, neuroinflammation and progressive nerve dysfunction. MAIN BODY: This review synthesizes evidence that hyperglycaemia, lipotoxicity and microvascular stress impair electron transport, oxidative phosphorylation and mitochondrial DNA stability, leading to excessive reactive oxygen species generation, calcium dyshomeostasis, mitochondrial permeability transition pore opening and maladaptive metabolic reprogramming. Disrupted fission-fusion balance, defective axonal transport, impaired mitophagy and abnormal mitochondria-associated endoplasmic reticulum membranes further weaken mitochondrial quality control in long peripheral axons. These changes engage SARM1-related NAD+ depletion, inflammasome activation, cGAS-STING signalling, apoptosis and glial-neuronal metabolic failure, thereby connecting bioenergetic collapse with pain sensitisation, distal axonal degeneration and autonomic dysfunction. Across painful and painless diabetic peripheral neuropathy, corneal small-fibre neuropathy, autonomic neuropathy and diabetes-related central nervous system injury, mitochondrial mechanisms appear shared, but endpoints and dominant cell types differ. Translationally, exercise and dietary strategies, metabolic regulators, SARM1 and calcium-pathway targeting, mitophagy modulation, mitochondria-directed antioxidants, and traditional Chinese medicine or natural products are discussed as metabolism-oriented interventions. Current evidence supports target engagement in experimental systems, but human validation, tissue exposure data, structural nerve endpoints and high-quality disease-modifying trials remain insufficient.

conclusionMitochondrial dysfunction functions as a core pathogenic hub-rather than the sole cause-linking substrate overload, redox imbalance, calcium stress, organelle quality-control failure, inflammatory signalling, and axonal degeneration in diabetic neuropathy. The most actionable translational path is not symptomatic antioxidant use alone but biomarker-guided, mechanism-stratified trials that connect mitochondrial target modulation with small-fibre structure, nerve function, safety, and patient-centred outcomes. SEARCH STRATEGY AND EVIDENCE SELECTION: For this narrative review, PubMed was searched from database inception to 1 August 2026, supplemented by backward reference screening of relevant original studies and recent reviews. Search terms included "diabetic neuropathy", "diabetic peripheral neuropathy", "mitochondria", "oxidative phosphorylation", "oxidative stress", "mitophagy", "SARM1", "NLRP3", "cGAS-STING", and "mitochondria-associated endoplasmic reticulum membranes", alone and in combination. English-language original mechanistic, translational, observational, and interventional studies were prioritised; recent high-quality reviews were used for context and to identify primary studies. Evidence from other neurological disorders was retained only when direct DN evidence was limited and the study clarified biological plausibility. Because this is a narrative review, no formal risk-of-bias tool or GRADE assessment was applied; human, animal, and cellular evidence and major translational limitations are instead distinguished explicitly.