Selective Disruption of Drp1-Independent Mitophagy and Mitolysosome Trafficking by an Alzheimer's Disease Relevant Tau Modification in a Novel C. elegans Model.

Accumulation of inappropriately phosphorylated tau into neurofibrillary tangles (NFT) is a defining feature of Alzheimer's disease (AD), with Tau pT231 being an early harbinger of tau pathology. Previously, we demonstrated that expressing a single genomic copy of human phosphomimetic mutant tau (T231E) in C. elegans drove age-dependent neurodegeneration. A critical finding was that T231E, unlike wild type tau, completely and selectively suppressed oxidative stress-induced mitophagy. Here, we used dynamic imaging approaches to analyze T231E-associated changes in mitochondria and mitolysosome (ML) morphology, abundance, trafficking, and stress-induced mitophagy as a function of mitochondrial fission mediator Drp1, which has been demonstrated to interact with hyper phosphorylated tau and contribute to AD pathogenesis, as well as Pink1, a well-recognized mediator of mitochondrial quality control that works together with Parkin to support stress-induced mitophagy. T231E impacted both mitophagy and ML neurite trafficking with exquisite selectivity, sparing macroautophagy as well as lysosome and autolysosome trafficking. Both oxidative-stress induced mitophagy and the ability of T231E to suppress it were independent of drp-1, but at least partially dependent on pink-1. Organelle trafficking was more complicated, with drp-1 and pink-1 mutants exerting independent effects, but generally supported the idea that the mitophagy phenotype is of greater physiologic impact in T231E. Collectively, our results refine the mechanistic pathway through which T231E causes neurodegeneration, demonstrating pathologic selectivity for mutations that mimic tauopathy-associated post-translational modifications, physiologic selectivity for organelles that contain damaged mitochondria, and molecular selectivity for Drp1-independent, Pink1-dependent, perhaps adaptive, mitophagy.