Orchestrating mitochondria in neurons: Cytoskeleton as the conductor

Abstract

Mitochondria are crucial to support synaptic activity, particularly through ATP production and Ca²⁺ homeostasis. This implies that mitochondria need to be well distributed throughout the different neuronal sub-compartments. To achieve this, a tight and precise regulation of several neuronal cytoskeleton players is necessary to transport and dock mitochondria. As post-mitotic cells, neurons are highly dependent on mitochondrial quality control mechanisms and several cytoskeleton proteins have been implicated in mitophagy. Therefore, all of these processes are orchestrated by the crosstalk between mitochondria and the neuronal cytoskeleton to form a coordinated and tuned symphony.

Keywords: docking; mitochondria; neuronal cytoskeleton; synapse; transport.

Figure 1

Mechanisms of mitochondrial transport and docking in mammalian neurons (a) Dendritic transport. Dendritic microtubules have mixed polarity; therefore, dynein and kinesin undergo anterograde or retrograde transport. Although, in dendrites, mitochondrial transport is mainly mediated by dynein, TRAK2, and possibly Miro1; kinesin, TRAK1, and Miro2 may also be involved. (b) Axonal transport. Axonal microtubules have their minus‐ends directed to the cell body and the plus‐ends toward the periphery. Kinesin is responsible for the anterograde transport, mediated by Syntabulin, TRAK1 and possibly Miro2. Dynein is responsible for retrograde transport, mediated by the dynactin subunit, actr10 or an unknown adaptor, possibly VDAC1. (c) Mitochondrial docking dependent on Ca²⁺. Miro is able to sense Ca²⁺ levels, promoting entry of Ca²⁺ to mitochondria through the MCU, which leads to conformational changes in Miro and disruption of the Miro‐MCU complex. Elevated Ca²⁺ activates HDAC6, leading to deacetylation of Miro. Together, these mechanisms promote the detachment of mitochondria from kinesin. (d) Mitochondrial docking dependent on ADP and Glucose. Synapses are regions with high ATP consumption and increased levels of ADP. ADP can bind to kinesin inhibiting its motor function. Synaptic activity also promotes entry of glucose, which activates O‐GlcNAc transferase (OGT), leading to O‐GlcNAcylation of Milton. Together, these mechanisms promote the detachment of mitochondria from kinesin. (e) Mitochondrial anchoring at synapse. When mitochondria detach from kinesin, they can either undergo microtubule‐dependent docking, mediated by Syntaphilin; or actin‐dependent docking, through a myosin

Figure 2

How neurons deal with distally damaged mitochondria: Mild versus severe damage(a) Upon mild damage, mitochondria in the vicinity of synapses detach from Syntaphilin and are transported retrogradely to the cell body for degradation. (b) Upon severe damage, mitochondria trigger local mitophagy, through the PINK1/Parkin pathway. When mitochondria are unhealthy, PINK1 accumulates on the mitochondrial membrane (OMM) and phosphorylates Parkin, which in turn ubiquitinates several mitochondrial substrates, including Miro. Ubiquitinated mitochondria are engulfed by autophagosomes, which can either undergo retrograde transport or local fusion with lysosomes