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.