A Mitochondria-Cluster At The Proximal Axon Initial Segment Controls Axodendritic TAU Trafficking In Rodent Primary And Human iPSCderived Neurons

Loss of neuronal polarity and missorting of the axonal microtubule-associated protein TAU are hallmarks of Alzheimer’s disease (AD) and related tauopathies. Impairment of mitochondrial function is causative for various neurogenetic mitochondriopathies, but the role of mitochondria in tauopathies and in axonal TAU-sorting is still unclear. The axon initial segment (AIS) is vital for maintaining neuronal polarity and proper sorting of TAU. Here, we aimed to investigate the role of mitochondria in the AIS regarding the maintenance of TAU polarity. Using global mitochondria impairment, but also live-cell-imaging and photoactivation methods, we specifically tracked and selectively impaired mitochondria in the AIS in primary mouse and human iPSC-derived neurons, and measured the subsequent missorting of TAU. We observed that global application of mitochondrial toxins efficiently induced tauopathy-like missorting, indicating involvement of mitochondria in TAU polarity. Mitochondria show a biased distribution within the AIS, with a proximal cluster and relative absence in the central AIS. The mitochondria of this cluster are largely immobile and only sparsely participate in axonal mitochondria-trafficking. Locally constricted impairment of only the AIS-mitochondria-cluster leads to detectable increases of somatic TAU, reminiscent of AD-like TAU-missorting. Here, we provide first evidence that the mitochondrial distribution within the proximal axon is biased towards the proximal AIS and that proper function of this newly described mitochondrial cluster may be essential for the maintenance of TAU neuronal polarity. This strengthens the role of mitochondrial impairment as an upstream event and therapeutic target in the pathological cascade leading to TAU missorting and consequent neuronal dysfunction.