Disease‐associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria

Abstract

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.

Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency

“…Therefore, we hypothesized that MMUT deficiency might compromise the PINK1/Parkin-mediated priming of MMA stressed mitochondria to autophagic-lysosomal degradation. Due to the lack of commercially available antibodies able to detect endogenous PINK1, we resorted to the translocation of Parkin to damaged mitochondria-a key downstream step following the activation of PINK1-as a bona fide reporter to assess the PINK1/Parkinpriming mechanisms 22,41,42 . We labelled the mitochondrial network by transducing both control and MMA cells with an adenovirus that expresses the mitochondrially targeted green fluorescent protein (Ad-mito-GFP).…”

“…We labelled the mitochondrial network by transducing both control and MMA cells with an adenovirus that expresses the mitochondrially targeted green fluorescent protein (Ad-mito-GFP). Twenty-four hours posttransduction, we exposed the mt-GFP-expressing cells to Rotenone (5 μM for 4 h) and scored the translocation of Parkin to mito-GFP-flagged mitochondria by confocal microscopy 42 . Using a validated α-Parkin antibody (see Supplementary Fig.…”

Mechanisms and roles of mitophagy in neurodegenerative diseases

“…Besides, it was recently found that hTau can prevent the intracytoplasmic translocation of Parkin to the mitochondrial membrane and inhibit mitophagy in nematode models, while such effect is independent of the changes in membrane potential. On the other hand, the NH2‐terminal fragment of tau can regulate Parkin and UCHL‐1 through inhibiting the ANT‐1‐dependent ADP/ATP exchange, suppress mitochondrial autophagy, and mediate synaptic degeneration in AD …”

Astrocytic IGF-1 and IGF-1R Orchestrate Mitophagy in Traumatic Brain Injury

“…IGF-1 has shown to increase the mitophagy via activating AMPK signal [11]. We have shown mitophagy is impaired in the chronic stage of TBI [12,13], and accordingly we predict that this might be due to the lower IGF-1 status after TBI, as tau phosphorylation can disrupt the mitophagy [14]. We also nd astrocytes have a supporting role for neurons and protect against excitotoxic injury with IGF-1 dependent [15,16].…”