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Review
. 2023 Aug:81:102747.
doi: 10.1016/j.conb.2023.102747. Epub 2023 Jun 29.

Mitochondrial regulation of local supply of energy in neurons

Guillermo López-Doménech  1 , Josef T Kittler  2
Affiliations
Review

Mitochondrial regulation of local supply of energy in neurons

Guillermo López-Doménech et al. Curr Opin Neurobiol. 2023 Aug.

Abstract

Brain computation is metabolically expensive and requires the supply of significant amounts of energy. Mitochondria are highly specialized organelles whose main function is to generate cellular energy. Due to their complex morphologies, neurons are especially dependent on a set of tools necessary to regulate mitochondrial function locally in order to match energy provision with local demands. By regulating mitochondrial transport, neurons control the local availability of mitochondrial mass in response to changes in synaptic activity. Neurons also modulate mitochondrial dynamics locally to adjust metabolic efficiency with energetic demand. Additionally, neurons remove inefficient mitochondria through mitophagy. Neurons coordinate these processes through signalling pathways that couple energetic expenditure with energy availability. When these mechanisms fail, neurons can no longer support brain function giving rise to neuropathological states like metabolic syndromes or neurodegeneration.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1
Figure 1
Synaptic immobilization of mitochondria, Maintaining synaptic activity is an energetically expensive task. ATP is needed to regenerate the ion gradients responsible for neuronal excitability. Neurons use different mechanisms to ensure the presence of mitochondria near presynaptic sites to ensure that energy provision matches energy expenditure. One mechanism senses the rise in intracellular Ca2+ due to synaptic activation to stop mitochondria via anchorage by Syntaphilin (SNPH). This mechanism is supported by Myosin 6 phosphorylation dependent anchorage of mitochondria to the actin cytoskeleton which is mediated by AMPK and thus, is regulated by the energetic status of the cell. Myosin 5a (Myo5a) and Myosin 19 (Myo19) are other candidates to mediate actin dependent immobilization of mitochondria in synapses, being Myo19 known to be regulated by both ROS production and glucose availability. Mitochondria can also be stopped at the synapse by a mechanisms that senses high glucose levels driven by the increased abundance of glucose transporters. Glucose is used as a substrate to synthetize UDP-GlcNAc by the Hexosamine Biosynthetic Pathway. OGT uses UDP-GlcNAc to catalyze the O-GlcNAcylation of TRAK1, which stops mitochondrial motility and is coupled with the FHL2-dependent anchoring of mitochondria to the actin cytoskeleton.
Figure 2
Figure 2
Mitochondrial dynamics, biogenesis and mitophagy, Neurons regulate mitochondrial remodelling locally in response to the cellular context. Mild energetic stress favours mitochondrial fusion through the AMPK or mTOR pathways. Growth Factors and synaptic activity, through activation of PKA and Calcineurin respectively, may also stimulate mitochondrial elongation by inhibiting the translocation of Drp1 to the mitochondrial membrane and, thus, inhibiting fission. In contrast, Drp1 and MFF activity are critical to ensure that short mitochondria is produced to enter in the axon and populate presynaptic terminals. In addition, similar signalling pathways, like AMPK or CaMKK2, activated by the energetic state or synaptic communication respectively, can also stimulate mitochondrial biogenesis through activation of PCG1. Continuous synaptic activity giving rise to elevated levels of ROS and energy depletion in axons can activate the fission of defective mitochondria though the strong activation of AMPK, which mediates fission instead of fusion by phosphorylation of MFF and recruitment of Drp1 to the mitochondrial membrane. This process help removed dysfunctional mitochondria by coupling this fission to the retrograde mitochondrial transport machinery to deliver these defective mitochondria to the soma where it will fuse to lysosomes and be degraded.
Figure 3
Figure 3
Regulation of cristae structure by the transport machinery, Mitochondrial ultrastructure is linked to mitochondrial function. Opa1 and the MICOS complexes are two critical regulators of mitochondrial cristae morphology and thus can potentially control mitochondrial energy production. It has recently been identified a molecular bridge between the MICOS complex and the mitochondrial transport machinery that couples both mitochondrial membranes to the transport pathway. This bridge may act as a sensor of intramitochondrial oxidation and thus influence the transport of the organelle. Likewise, the signalling pathways governing mitochondrial trafficking might impact mitochondrial ultrastructure and ultimately energy production.
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