Dysregulation of a novel autophagosome-mitochondria contact contributes to tauopathy-related neurodegeneration by disrupting autophagy.

Beyond their role in energy production, mitochondria also interact with other organelles through forming membrane contacts that serve as central hubs of cellular metabolism and signaling. Aberrant mitochondria-organelle communication has been implicated in various neurodegenerative diseases, but the underlying mechanisms and their pathological consequences remain poorly understood. Here, we reveal that tauopathy synapses exhibit excessive tethering of autophagosome/autophagic vacuole (AV)-mitochondria (Mito) contacts, driven by mitochondrial bioenergetic deficit-induced hyperactivity of adenosine monophosphate-activated protein kinase (AMPK) that results in accelerated turnover of the contact release factor TBC1D15. Such defects consequently disrupt autophagy-mediated clearance of MAPT/tau by preventing AV retrograde transport. Strikingly, elevating TBC1D15 levels normalizes AV-Mito contact dynamics and restores autophagy activity, thereby mitigating MAPT/tau pathology and ameliorating neurodegeneration and cognitive impairment in tauopathy mice. Together, these findings establish bioenergetic deficits and the resulting AV-Mito hyper-tethering as a critical mechanism driving autophagy dysfunction and pathological MAPT/tau buildup in tauopathy neurons and highlight TBC1D15-modulated AV-Mito contact release and autophagy as promising therapeutic targets for tauopathies, including Alzheimer disease.Abbreviation: AAV, adeno-associated virus; AD, Alzheimer disease; AMPK, adenosine monophosphate-activated protein kinase; AV, autophagosome/autophagic vacuole; CLEM, correlative light and electron microscopy; cryo-ET, cryo-electron tomography; FTD, Frontotemporal dementia; GAP, GTPase-activating protein; Mito, mitochondria; NFT, neurofibrillary tangle; OE, overexpression; Phospho-MAPT/tau, phosphorylated MAPT/tau; SQSTM1/p62, sequestosome 1; TEM, transmission electron microscopy; Tg, transgenic.