Tau-induced mitochondrial reverse electron transport drives neurodegeneration

Li and colleagues describe a mitochondrial mechanism linking tau pathology to neuronal damage. In flies, mice, human brain tissue, and human iPSC-derived neurons, tau entered mitochondria under stress when phosphorylated. It bound the complex I subunit NDUFS3 and promoted mitochondrial reverse electron transport. The process increased reactive oxygen species, lowered the NAD+/NADH ratio, and further promoted tau hyperphosphorylation. Tau depletion eliminated stress-induced reverse electron transport and improved resilience. In tauopathy models, the experimental compound CPT blocked the tau-NDUFS3 interaction. CPT reduced neuroinflammation and neurodegeneration, improved behavioral performance, and extended lifespan in stressed flies. The same direction of effect appeared in human neuronal models carrying pathogenic tau mutations. This is a strong mechanistic paper with cross-species validation. It is not a human treatment trial. CPT is an experimental compound and has not entered clinical testing. The NAD+/NADH result is mechanistic, not evidence that oral NAD precursors treat tauopathies. The paper matters for longevity biology because it identifies a stress-sensitive mitochondrial loop that may become more damaging with age. The immediate implication is a target for drug development, not a supplement recommendation.

RET regulation thus represents a previously unrecognized normal function of tau that becomes pathological in disease, providing a therapeutic target for various conditions characterized by tau abnormalities and mitochondrial dysfunction.