TBK1 Loss Drives Motor Neuron Death Through Impaired Mitophagy and Metabolic Collapse

This hypothesis proposes that loss-of-function mutations in TBK1 contribute to ALS pathogenesis primarily through disrupted mitochondrial quality control in motor neurons, leading to bioenergetic failure and selective neuronal death. TBK1 normally phosphorylates autophagy receptors OPTN and p62, which are essential for targeting damaged mitochondria for mitophagy. When TBK1 function is lost, defective mitochondria accumulate in motor neurons, causing oxidative stress, ATP depletion, and ultimately cell death. Supporting evidence includes phospho-proteome profiling in human neurons (Smeyers et al., Cell Rep 2025) showing that ALS/FTD-associated TBK1 substrates are predominantly neuronal autophagy proteins (FIP200, OPTN, p62) rather than inflammatory mediators. Motor neurons are particularly vulnerable due to their high metabolic demands, long axonal projections requiring extensive mitochondrial transport, and limited regenerative capacity. The 2025 Nat Commun study, while highlighting microglial changes, may reflect secondary neuroinflammation responding to primary motor neuron damage rather than the initiating pathogenic event. Human genetic evidence supports this model: TBK1 haploinsufficiency causes familial ALS/FTD, and mutations in other mitophagy-related genes (OPTN, p62/SQSTM1) also cause ALS, suggesting convergent pathways. Contradictory evidence includes the Cell (2018) study linking TBK1 to RIPK1-driven inflammation, but this inflammatory axis may be secondary to metabolic dysfunction. Additionally, while TDP-43 pathology activates cGAS-STING signaling (Cell 2020), this could represent a downstream consequence of mitochondrial DNA release from damaged mitochondria rather than the primary pathogenic mechanism. This model positions mitochondrial dysfunction as the central pathogenic hub, with neuroinflammation and other ALS hallmarks arising secondarily from bioenergetic collapse.