The Interplay of Axonal Energy Homeostasis and Mitochondrial Trafficking and Anchoring

Abstract

Mitochondria are key cellular power plants essential for neuronal growth, survival, function, and regeneration after injury. Given their unique morphological features, neurons face exceptional challenges in maintaining energy homeostasis at distal synapses and growth cones where energy is in high demand. Efficient regulation of mitochondrial trafficking and anchoring is critical for neurons to meet altered energy requirements. Mitochondrial dysfunction and impaired transport have been implicated in several major neurological disorders. Thus, research into energy-mediated regulation of mitochondrial recruitment and redistribution is an important emerging frontier. In this review, I discuss new insights into the mechanisms regulating mitochondrial trafficking and anchoring, and provide an updated overview of how mitochondrial motility maintains energy homeostasis in axons, thus contributing to neuronal growth, regeneration, and synaptic function.

Figure 1. Motors/adaptors and anchoring protein play the opposite roles in regulating axonal mitochondrial motility

Long-distance axonal mitochondrial transport is driven by MT-based molecular motors: the plus-end directed kinesin and the minus-end directed dynein. Axonal MTs are uniformly arranged so that their plus-end is directed distally and the minus-end is toward the soma; thus, most kinesin motors move toward distal axons while dynein motors mediate retrograde transport toward the soma. The kinesin-1 family proteins (KIF5A, KIF5B, and KIF5C) are the main motor driving mitochondrial transport in neurons. Kinesin-1 motors interact with mitochondria through adaptor proteins. Axonal mitochondria also deploy an anchoring mechanism in addition to motor-driven transport. SNPH acts as a “static anchor” specific for axonal mitochondria. SNPH arrests mitochondrial transport by anchoring them to MTs. In CNS axons, the majority of mitochondria remain stationary, while approximately 20–30% are motile. Motile mitochondria can become stationary and stationary ones can be remobilized. The balance of motile versus stationary axonal mitochondria depends on the relative action of the motor/adaptor and SNPH.

Figure 2. Synaptic activity regulates mitochondrial transport

(A, B) Miro-Ca²⁺ sensing models. Miro is a mitochondrial outer membrane protein with two Ca²⁺-binding EF hands. By sensing cytosolic Ca²⁺ levels, Miro arrests mitochondria at activated synapses by inactivating KIF5 transport machineries. When a trafficking mitochondrion passes through an active synapse, elevated Ca²⁺ binds to Miro and induces its conformational changes, thus disrupting the complexes of KIF5-Trak-Mito complex [35, 44]. Through this mechanism, mitochondria are immobilized at activated synapses. Two alternative models were proposed on whether (A) the KIF5 motor remains associated with arrested mitochondria or (B) is disconnected with the organelle upon immobilization. It should be noted that two recent genetic studies showed that the loss of Miro1 in neurons does not inhibit the Ca²⁺-dependent arrest of remaining mitochondria [46, 47], thus raising the possibility that activity-dependent mitochondrial immobilization may require a static anchoring mechanism. (C) Engine-switch and brake model. When a motile mitochondrion passes by an activated synapse, the anchoring protein SNPH responds to elevated Ca²⁺ (stop sign) and switches off the engine (motor) and places a brake on mitochondrion, thereby arresting mitochondria on the MT-track. When the Ca²⁺ signal is removed, the cargo-loaded motor-adaptor complexes can be quickly re-activated to drive the mitochondrion to new active synapses. This engine-switch and brake model suggests an interplay between the motor-adaptor transport complex and the anchoring protein SNPH [37]. Through this mechanism, neurons effectively regulate axonal mitochondrial distribution in response to changes in energy-demanding synaptic activity.

Figure 3. Mitochondrial motility influences energy homeostasis and presynaptic strength

(A) A stationary mitochondrion retained within a presynaptic bouton constantly supplies ATP to support various presynaptic functions such as: establishing the proton gradient necessary for neurotransmitter loading; removing Ca²⁺ from nerve terminals; powering SV transport from reserve pools to release sites; and driving SV exo- and endocytotic recycling, thus maintaining presynaptic strength. (B) For a presynaptic terminal lacking an anchored mitochondrion, ATP is mainly supplied through diffusion from mitochondria outside synapses. When a mitochondrion moves closer, more ATP supplies the synapse; when a mitochondrion moves away, less ATP supplies the synapse. Thereby, a motile mitochondrion passing through this presynaptic bouton dynamically alters local ATP levels and influences ATP-dependent synaptic functions, thus leading to wide pulse-to-pulse variability of synaptic strength, particularly under increased energy demand during sustained synaptic activity.

Figure 4. Illustration of enhanced mitochondrial transport critical for mature neurons to regain axonal regenerative capacity

(A) An energy deficit is defined as insufficient ATP supply when mitochondria are damaged and/or there is increased energy consumption during regeneration. Mitochondrial damage by axonal injury and mature neuron-associated decline of mitochondrial transport collectively contribute to local energy deficits in injured axons, thus leading to regeneration failure. Energy deficits may reflect the intrinsic restriction of mature neurons to regenerate following injury. (B) Enhanced mitochondrial transport by deleting SNPH not only helps remove those dysfunctional mitochondria, but also replenishes healthy ones to the injured axons, thus recovering mitochondrial integrity and rescuing energy deficits. An enhanced local ATP supply is critical to meeting the metabolic requirements of axon regeneration. Thus, activating an intrinsic “growth program” requires the coordinated recovery of energy deficits by enhancing mitochondrial transport. Such coordinated regulation may represent a valid therapeutic strategy to facilitate nerve regeneration and functional recovery after injury and diseases.