Accumulation of the protein tau characterises Alzheimer's disease and other tauopathies, including familial forms of frontotemporal dementia (FTD) that carry pathogenic tau mutations. Another hallmark feature of these diseases is the accumulation of dysfunctional mitochondria. Although disease‐associated tau is known to impair several aspects of mitochondrial function, it is still unclear whether it also directly impinges on mitochondrial quality control, specifically Parkin‐dependent mitophagy. Using the mito‐QC mitophagy reporter, we found that both human wild‐type (hTau) and FTD mutant tau (hP301L) inhibited mitophagy in neuroblastoma cells, by reducing mitochondrial translocation of Parkin. In the Caenorhabditis elegans nervous system, hTau expression reduced mitophagy, whereas hP301L expression completely inhibited it. These effects were not due to changes in the mitochondrial membrane potential or the cytoskeleton, as tau specifically impaired Parkin recruitment to defective mitochondria by sequestering it in the cytosol. This sequestration was mediated by aberrant interactions of Parkin with the projection domain of tau. As mitochondria are dysfunctional in neurodegenerative conditions, these data suggest a vicious cycle, with tau also inhibiting the degradation of damaged mitochondria.
Although mitochondria are ubiquitous organelles, they exhibit tissue-specific morphology, dynamics and function. Here, we describe a robust approach to isolate mitochondria from specific cells of diverse tissue systems in Caenorhabditis elegans. Cell-specific mitochondrial affinity purification (CS-MAP) yields intact and functional mitochondria with exceptional purity and sensitivity (>96% enrichment, >96% purity, and single-cell and single-animal resolution), enabling comparative analyses of protein and nucleic acid composition between organelles isolated from distinct cellular lineages. In animals harbouring a mixture of mutant and wild-type mitochondrial genomes, we use CS-MAP to reveal subtle mosaic patterns of cell-type-specific heteroplasmy across large populations of animals (>10,000 individuals). We demonstrate that the germline is more prone to propagating deleterious mitochondrial genomes than somatic lineages, which we propose is caused by enhanced mtDNA replication in this tissue.
In the version of this Technical Report originally published, chromosome representations (indicated by black lines) were missing from Fig. 2a due to a technical error. The corrected version of Fig. 2a is shown below. This has now been amended in all online versions of the Technical Report.
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