Fig. 1

Selected aspects of cytoskeletal transport and mitochondrial dynamics during homeostasis. a The interaction between ER-bound VAPB and mitochondria-bound PTPIP51 allows calcium ions to cycle between these organelles in order to maintain mitochondrial integrity, homeostasis and ATP production. b Association of TDP-43 with the pre-mRNA of STMN2 prevents the inclusion of a cryptic exon. As a result, full-length, mature STMN2 is produced, which modulates the polymerization and disassembly of microtubules. c The kinase PKN1 phosphorylates the head-rod domain of neurofilaments, which prevents these filaments from forming dimers so that they can be transported towards the distal end of the axon. PKN1 also elevates the expression of neuronal glutamate transporters, such as EAAT3. d, e PINK1/PARKIN signaling acts as a molecular switch between anterograde and retrograde mitochondrial transport. d In healthy mitochondria, PINK1 is imported and cleaved by intramitochondrial proteases. The cleaved PINK1 is degraded by the proteasome but is also demonstrated to bind to Miro-kinesin complexes and facilitate anterograde transport. e On the other hand, PINK1 is not imported into damaged, depolarized mitochondria and is instead activated through dimerization and autophosphorylation. The active PINK1 promotes the degradation of kinesin-associated Miro, which arrests anterograde mitochondrial transport. Full-length PINK1 is demonstrated to facilitate retrograde transport; however, PINK1 is also able to promote degradation of dynein-associated Miro and inhibit transport altogether. Active PINK1 phosphorylates PARKIN. Together, these proteins phosphorylate and ubiquitinate proteins on the mitochondrion surface. The phospho-ubiquitin chains activate TBK1, which in turn phosphorylates and activates mitophagy adaptor proteins, such as OPTN, p62 and NDP52, which initiate the removal of damaged mitochondria through the process of mitophagy