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Table 4 The intricate relationship between MTs and axonal organelles

From: The model of local axon homeostasis - explaining the role and regulation of microtubule bundles in axon maintenance and pathology

MTs and cellular organelles display important and complex interdependencies. This becomes immediately apparent when considering that meaningful dynamics of any organelles will depend on MTs and their associated motor proteins (Fig. 3C and D). Vice versa, organelles play crucial roles in cellular physiology directly or indirectly relevant for MTs, as outlined in the following for mitochondria:
(1) Mitochondria are the main source for ATP [195], required to fuel multiple processes relevant for MT dynamics and regulation (red stippled arrows in Fig. 3); these include actin assembly and dynamics [196, 197], phosphorylation of MT regulators [198], GTP production required for signalling events and MT polymerisation [37, 199, 200], MT severing [201], as well as MT-motor protein dynamics ([40]; but note that vesicular transport uses local glycolysis to generate its own ATP; [202, 203]; yellow star in Fig. 3 A).
(2) The mitochondrial surface is an important signalling platform potentially required to orchestrate MT regulation locally (not shown in Fig. 3; [204]).
(3) Mitochondria cooperate with endoplasmic reticulum in the regulation of intracellular free calcium (yellow cloud in Fig. 3; [205, 206]) which has direct impact on MT regulators (e.g. spectraplakins, tau, kinesins [207, 208]; or even on MTs themselves [209]).
(4) Mitochondria collaborate with peroxisomes in the regulation of reactive oxygen species ('ROS' in Fig. 3; [210, 211]), which have known effects on MT regulation [212]. If excessive amounts of the wrong ROS species are produced upon transport-induced mitochondrial damage or dysregulation of the mitochondria-peroxisome system, this causes oxidative stress as a major path to axon pathology [67, 211, 213]. Causative relationships between MTs and oxidative stress can be demonstrated experimentally: for example the MT-stabilising drug epothilone B rescues pathology caused by oxidative stress caused by peroxisome transport deficiencies in a human iPSC (induced pluripotent stem cell) model of SPG4 (spastin-linked spastic paraplegia 4; [214]), suggesting that MTs might be the cause for the transport deficit in the first place.
Also other organelles impact on MTs. For example, the endoplasmic reticulum has multiple roles in lipidogenesis and protein synthesis but also calcium homeostasis [44], and the endo-lysosomal and proteasome-ubiquitination systems are required for proteostasis known to be relevant for MTs and axonal transport [215,216,217].
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