Fig. 5.

MAMs control mitochondrial dynamics. Endoplasmic reticulum (ER)-mitochondria contact sites are involved in mitochondrial fission and transport of mitochondria along cytoskeletal tracks. During fission, mitochondria-associated membranes (MAMs) determine the site of scission by contributing to the mitochondrial constriction required for dynamin-related protein 1 (Drp1) assembly. This constriction is accomplished through the actin-modulating activity of Spire1C and inverted forming 2 (INF2) at the membrane contact sites (MCSs). At least two other MAM proteins, syntaxin 17 (STX17) and Rab32, contribute to the regulation of mitochondrial fission by controlling Drp1 activity. Mitochondrial transport is primarily mediated by the mitochondrial Rho GTPases 1 and 2 (Miro1/2), which connect the mitochondria to motor proteins such as kinesins through the trafficking kinesin protein (TRAK) adaptor proteins. Miro depends on mitofusin1 and 2 (MFN1/2) to facilitate transport, and PTEN-induced putative kinase 1 (PINK1)-Parkin-dependent ubiquitination of Miro1/2 and MFN2 blocks mitochondrial movement. In zones of high calcium concentrations, such as those that occur at MAMs, calcium binding to the Miro1/2 EF-hand motifs releases the mitochondria from the cytoskeleton and halts their migration. The P56S mutation in VAMP-associated protein B and C (VAPB), which results in a higher degree of ER-mitochondria contact and calcium crosstalk, consequently results in axonal transport defects of mitochondria