Mitochondrial Modulation as a Therapeutic Entry Point in Neurodegeneration

Abstract

Highlights What are the main findings? The pathogenic and therapeutic significance of mitochondrial dysfunction varies across disorders and disease stages, acting as a pathway-proximal driver in some contexts and an amplifier of neuronal vulnerability in others. Broad antioxidant approaches have generally failed to modify clinical progression, whereas mechanism-specific strategies may offer greater translational potential in biologically defined populations. What are the implications of the main findings? Mitochondria-directed therapies require mechanism-informed trial design, biomarker-enriched patient selection, and disease-stage-appropriate treatment timing. Future trials should distinguish pharmacodynamic target engagement from clinical benefit and evaluate mitochondrial modulation primarily as a precision-guided or adjunctive strategy. Abstract Mitochondrial dysfunction is a recurrent but context-dependent feature of neurodegenerative disease, and its position in the pathogenic cascade differs fundamentally between disorders. This narrative review argues that this heterogeneity, rather than mitochondrial biology itself, determines therapeutic tractability. We synthesize evidence on mitochondrial regulation of neuronal development, organelle quality control, redox signaling and neuroinflammation; on oxidative biomarkers, whose clinical use remains constrained by limited disease specificity, methodological heterogeneity and insufficient longitudinal validation; and on therapeutic strategies ranging from antioxidants and NAD+ augmentation to mitochondrial genome engineering, targeted delivery and organelle transfer. A consistent pattern emerges across these domains: broadly acting interventions have repeatedly failed in sporadic disease, whereas the strongest translational signals arise where mitochondrial dysfunction is genetically anchored and pathway-proximal. Mitochondrial modulation is therefore unlikely to provide a universal disease-modifying strategy, but remains a useful, carefully targeted addition for patient groups identified by genetic or specific biological markers.