Mitochondrial heterogeneity and homeostasis through the lens of a neuron

Abstract

Mitochondria are vital organelles with distinct morphological features and functional properties. The dynamic network of mitochondria undergoes structural and functional adaptations in response to cell-type-specific metabolic demands. Even within the same cell, mitochondria can display wide diversity and separate into functionally distinct subpopulations. Mitochondrial heterogeneity supports unique subcellular functions and is crucial to polarized cells, such as neurons. The spatiotemporal metabolic burden within the complex shape of a neuron requires precisely localized mitochondria. By travelling great lengths throughout neurons and experiencing bouts of immobility, mitochondria meet distant local fuel demands. Understanding mitochondrial heterogeneity and homeostasis mechanisms in neurons provides a framework to probe their significance to many other cell types. Here, we put forth an outline of the multifaceted role of mitochondria in regulating neuronal physiology and cellular functions more broadly.

Fig. 1 |. Mitochondrial network in different cell types.

The shape and composition of the mitochondrial network are tailored to match cell-type-specific energy demands. a, In neurons, mitochondria form a long and connected network at the somatodendritic region. In contrast, axonal mitochondria occupy a smaller volume as discrete units. b, In cardiomyocytes, mitochondria form a dense and perfectly aligned network and occupy >30% of the cytoplasmic volume. c, Mitochondria are largely distributed evenly in fibroblasts, forming an interconnected network near the nucleus and a smaller motile pool at the cell periphery. d, In lymphocytes, mitochondria are relatively homogeneously distributed in a small cytoplasmic volume. Mitochondrial network and size change in response to polarization and activation for metabolic adaptation^,. e, In adipocytes, mitochondria occupy most of the cytoplasmic volume. Subpopulations of metabolically specialized mitochondria (grey; LDM) are associated with lipid droplets (pink).

Fig. 2 |. Mitochondrial morphology and localization in neurons.

a, A typical neuron, composed of a cell body (soma), dendrites with multiple dendritic spines, and an axon with presynaptic boutons. b, Scheme depicting a synapse. Synaptic mitochondria locally generate ATP to sustain synaptic activity. The localization of mitochondria at the synapses is regulated by microtubule-based long-distance axonal transport and actin-based capture mechanisms. In addition to mitochondria, activity-dependent glucose uptake and local glycolysis enzymes support synaptic ATP synthesis.

Fig. 3 |. Molecular mechanisms underlying mitochondrial trafficking and positioning.

a, Schematic representation of currently known molecular machineries for microtubule-based mitochondrial movement. Besides Miro and Milton, several other proteins have been found to recruit KHC to mitochondria, which include syntabulin, fasciculation and elongation protein-zeta 1 (FEZ1)^,, and RAN-binding protein 2 (RANBP2). Miro, metaxin (a group of OMM proteins), and KLC can form a complex to aid in KHC-dependent mitochondrial movement. Both KIF1Bα and KLP6 can interact with KIF1-binding protein (KBP), which is essential for mitochondrial localization^,. Miro–Milton–dynein acts as the core motor–adapter complex for retrograde movement^,. b, Mechanisms underlying mitochondrial arrest. High Ca+ influxes as a result of synaptic activity dissociate mitochondria from microtubules by changing the conformation of the KHC–Milton–Miro complex^,. In axons, syntaphilin can anchor axonal mitochondria onto microtubules close to presynaptic boutons^,. c, Synaptic activity drives mitochondria into presynaptic boutons or postsynaptic spines via actin-mediated movement. d, Mitochondria stay where glucose concentrations are higher via Milton–OGT–FHL2-mediated docking.

Fig. 4 |. Mitochondrial quality-control pathways.

Future research is needed to unravel which quality-control pathways are implemented at individual synapses. a, Misfolded or defective mitochondrial proteins can be repaired or cleared by mitochondrial proteases, chaperones, or the ubiquitin–proteasome system. OMM, outer mitochondrial membrane. IMM, inner mitochondrial membrane. IMS, intermembrane space. b, Piecemeal removal. Mitochondrial stress can be alleviated and damaged mitochondrial portions can be removed by the biogenesis of mitochondrial-derived vesicles (MDVs) during various stress responses or at steady state^–,,, mitochondrial-derived compartments (MDCs) under amino acid stress, structures positive for OMM (SPOTs) under protein import or infection stress, or mitochondrial nucleoid-enriched autophagosomes (APs) under the basal condition. ER, endoplasmic reticulum. c, The entire damaged mitochondria can be digested through mitophagy. The scheme shows one mitophagy pathway that is dependent on PINK1 and parkin. d, Mitochondria also undergo fission-and-fusion to discard or exchange materials^,,. MFF, mitochondrial fission factor. Figures adapted with permission from: a, ref. , Springer Nature Limited; b, ref. , Cell Press; c, ref. , Springer Nature Limited; d, ref. , Elsevier.