Tau-induced mitochondrial reverse electron transport drives neurodegeneration.

Tau regulates mitochondrial reverse electron transport (RET), which produces excess reactive oxygen species and is linked to neurodegeneration in tauopathies.

• Why it matters: Understanding how tau abnormalities cause mitochondrial dysfunction is crucial for developing targeted therapies for tau-related neurodegenerative diseases.
• What they did: The study used flies, mice, and human iPSC-derived neurons to show that tau depletion prevents stress-induced RET, and that tau interacts with mitochondrial complex I subunit NDUFS3 to promote RET in a phosphorylation-dependent manner.
• The result: Inhibiting RET reduces tau toxicity across species, suggesting that targeting RET regulation may offer a therapeutic approach for conditions involving tau abnormalities and mitochondrial dysfunction.