Decreased anterograde transport coupled with sustained retrograde transport contributes to reduced axonal mitochondrial density in tauopathy neurons

Abstract

Mitochondria are essential organelle required for neuronal homeostasis. Mitochondria supply ATP and buffer calcium at synaptic terminals. However, the complex structural geometry of neurons poses a unique challenge in transporting mitochondria to synaptic terminals. Kinesin motors supply mitochondria to the axonal compartments, while cytoplasmic dynein is required for retrograde transport. Despite the importance of presynaptic mitochondria, how and whether axonal mitochondrial transport and distribution are altered in tauopathy neurons remain poorly studied. In the current study, we have shown that anterograde transport of mitochondria is reduced in P301L neurons, while there is no change in the retrograde transport. Consistently, axonal mitochondrial abundance is reduced in P301L neurons. We further studied the possible role of two opposing motor proteins on mitochondrial transport and found that mitochondrial association of kinesin is decreased significantly in P301L cells. Interestingly, fitting our experimental data into mathematical equations suggested a possible rise in dynein activity to maintain retrograde flux in P301L cells. Our data indicate that decreased kinesin-mediated transport coupled with sustained retrograde transport might reduce axonal mitochondria in tauopathy neurons, thus contributing to the synaptic deficits in Alzheimer’s disease (AD) and other tauopathies.

Common mechanisms underlying axonal transport deficits in neurodegenerative diseases: a mini review

“…It implies an interaction between α-Syn pathology and diminishing levels of kinesins in PD. In addition, as kinesin motors supply mitochondria to the axonal compartments and synapses, the reduction in kinesin levels further led to impaired anterograde axonal transport of mitochondria and ATP deficit in human iPSC (induced pluripotent stem cell)-derived PD neurons carrying α-Syn gene duplication ( Prots et al, 2018 ; Sabui et al, 2022 ). The understanding of pathological mechanisms of reducing kinesin expression in facilitating restoration of anterograde transport will improve spatial abnormal distribution and dysfunction of mitochondria in PD.…”

Re-energising the brain: glucose metabolism, Tau protein and memory in ageing and dementia

“…Metabolism and Tau pathology mutually influence the function of each other through the p38 MAPK pathway [50] and through the ability of Tau to alter mitochondria directly [57,61,62] . As such clear links are present between metabolism, cognitive dysfunction, and Tau pathology, OXPHOS and aerobic glycolysis are currently undervalued therapeutic avenues that could offer impactful treatment options for targeting Tau and amyloid-beta pathology alone.…”

“…Numerous physical links between Tau and mitochondria have been made. Mutant Tau has been shown to impair mitochondrial axonal transport in AD mouse models and human induced pluripotent stem cells (iPSCs) [57,58] ; human Tau (hTau) expression impairs mitochondrion fusion and fission in Drosophila and mouse neurons, and hTau mice [59,60] ; hTau or mutant Tau reduces mitochondrial quality control through mitophagy in N2a cells and C. elegans neurons [61] ; and mutant Tau directly reduces the mitochondrial membrane potential required for ATP-synthesis in triple transgenic mice [62] , or iPSC-derived neurons from people with Tau mutation causing frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) [63] .…”

Current Advances in Mitochondrial Targeted Interventions in Alzheimer’s Disease

“…Using different experimental settings, the authors were able to verify that Aβ’s effects on mitochondrial transport involve glycogen synthase kinase 3beta (GSK3β) signaling [ 108 ], a kinase with proven involvement in Aβ-induced anterograde axonal transport deficits through its interaction with kinesin light chains [ 109 ]. More recently, it was demonstrated that the overexpression of tau P301L in primary neurons inhibited kinesin recruitment to mitochondria, thus inhibiting the anterograde mitochondria’s movement towards the axon terminals [ 110 ]. Notably, the retrograde transport of mitochondria was not affected by P301L [ 110 ].…”

“…More recently, it was demonstrated that the overexpression of tau P301L in primary neurons inhibited kinesin recruitment to mitochondria, thus inhibiting the anterograde mitochondria’s movement towards the axon terminals [ 110 ]. Notably, the retrograde transport of mitochondria was not affected by P301L [ 110 ]. In fact, several data suggest the increased vulnerability of the anterograde axonal mitochondrial transport in comparison with the opposite retrograde movement in AD-related conditions [ 103 ].…”