A mitochondria cluster at the proximal axon initial segment controls axodendritic TAU trafficking in rodent primary and human iPSC-derived neurons

Abstract

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 mitochondriopathies, but the role of mitochondria in tauopathies and in axonal TAU-sorting is unclear. The axon-initial-segment (AIS) is vital for maintaining neuronal polarity, action potential generation, and—here important—TAU-sorting. Here, we investigate the role of mitochondria in the AIS for maintenance of TAU cellular polarity. Using not only global and local mitochondria impairment via inhibitors of the respiratory chain and a locally activatable protonophore/uncoupler, but also live-cell-imaging and photoconversion methods, we specifically tracked and selectively impaired mitochondria in the AIS in primary mouse and human iPSC-derived forebrain/cortical neurons, and assessed somatic presence of TAU. Global application of mitochondrial toxins efficiently induced tauopathy-like TAU-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 the AIS-mitochondria-cluster leads to detectable increases of somatic TAU, reminiscent of AD-like TAU-missorting. Mechanistically, mitochondrial impairment sufficient to induce TAU-missorting results in decreases of calcium oscillation but increases in baseline calcium, yet chelating intracellular calcium did not prevent mitochondrial impairment-induced TAU-missorting. Stabilizing microtubules via taxol prevented TAU-missorting, hinting towards a role for impaired microtubule dynamics in mitochondrial-dysfunction-induced TAU-missorting. We provide 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 polarity. Mitochondrial impairment may be an upstream event in and therapeutic target for AD/tauopathy.

The ANC-1 (Nesprin-1/2) organelle-anchoring protein functions through mitochondria to polarize axon growth in response to SLT-1

“…Previous work in cultured mammalian neurons has indicated that mitochondria cluster at the base of the proximal axon and that this cluster is important for axo-dendritic polarity [ 30 , 31 ]. These observations prompted us to ask if C .…”

“…Previous work has indicated that a cluster of mitochondria at the base of the proximal axon can regulate axo-dendritic polarity in mammalian neurons [ 30 , 31 ]. Our finding that ANC-1 is required to polarize axon growth and for clustering of mitochondria to the base of the proximal axon suggested the possibility that ANC-1 could function through mitochondria to polarize axon growth.…”

“…Previous work in cultured mammalian neurons has indicated that mitochondria cluster at the base of the proximal axon and that this cluster is important for axo-dendritic polarity [30,31]. These observations prompted us to ask if C. elegans ANC-1 could polarize axon growth by controlling the localization of mitochondria within the proximal ALM axon.…”

“…A key aspect to understand this process is to determine how mitochondria are localized to the correct location within the neuron to promote specific neurodevelopmental steps. For example, a cluster of immobile mitochondria have been observed at the base of the proximal axon and this cluster of mitochondria is required to establish neuronal polarity [ 30 , 31 ]. However, the mechanisms that cause mitochondria to localize to the base of the proximal axon are unknown.…”

Redox signaling and metabolism in Alzheimer's disease

“…Cofilin then translocates to the mitochondria, where it generates a drop in mitochondrial membrane potential, and cytochrome c release through promotion of the opening of the permeability transition pore (Kang and Woo, 2019). A very recent and interesting work has shown that a cluster of mitochondria belonging to the axon initial segment, and with particular characteristics and little motility, is important for Tau sorting (Figure 2D) (Tjiang and Zempel, 2022). It has been shown that ROS produced in mitochondria, such as H 2 O 2 , can generate Tau oligomer formation in a mouse model (Figure 2E) (Du et al, 2022).…”