Comprehensive review linking Complex I/CoQ-driven ETC dysfunction and supercomplex remodeling to elevated ROS, mtDNA/mtDAMP release, and activation of NLRP3, cGAS-STING, and TLR9 inflammatory pathways, and proposing therapeutic approaches such as ETC support, supercomplex stabilization, and…

Highlights mechanistic, druggable targets and biomarker opportunities directly relevant to Parkinson’s disease—offering actionable paths for repurposing, neuroprotective interventions, and translational studies that bridge mitochondrial dysfunction and neuroinflammation.

Neurodegenerative diseases share a mitochondrial-immune axis in which impaired oxidative phosphorylation reshapes neuronal metabolism and drives chronic inflammation. Complex I play a redox gatekeeper role at the coenzyme Q (CoQ) junction: catalytic defects, misassembly, or reverse electron transport over-reduce the CoQ pool, increase electron leak, and elevate ROS. How respiratory supercomplex plasticity (CI-CIII2, CIII2-CIVn, or CI-CIII2-CIVn) modulates carrier channelling, flux control, and ROS propensity through dynamic reorganization of the electron transport chain is highlighted. Excess ROS damages lipids and mitochondrial DNA, promoting the release of mitochondrial damage-associated molecular patterns s that activate NLRP3 inflammasome signalling, cGAS-STING-dependent interferon programs, and endosomal TLR9 pathways, establishing feed-forward loops between mitochondrial injury and neuroinflammation. Disease-focused sections integrate evidence from Parkinson's, Alzheimer's, amyotrophic lateral sclerosis, and Huntington's models, and map these mechanisms onto therapeutic opportunities spanning electron transport chain support, supercomplex stabilization, and consider mtDNA-sensing inflammatory nodes.