Mitochondrial transport serves as a mitochondrial quality control strategy in axons: Implications for central nervous system disorders

Abstract

Axonal mitochondrial quality is essential for neuronal health and functions. Compromised mitochondrial quality, reflected by loss of membrane potential, collapse of ATP production, abnormal morphology, burst of reactive oxygen species generation, and impaired Ca²⁺ buffering capacity, can alter mitochondrial transport. Mitochondrial transport in turn maintains axonal mitochondrial homeostasis in several ways. Newly generated mitochondria are anterogradely transported along with axon from soma to replenish axonal mitochondrial pool, while damaged mitochondria undergo retrograde transport for repair or degradation. Besides, mitochondria are also arrested in axon to quarantine damages locally. Accumulating evidence suggests abnormal mitochondrial transport leads to mitochondrial dysfunction and axon degeneration in a variety of neurological and psychiatric disorders. Further investigations into the details of this process would help to extend our understanding of various neurological diseases and shed light on the corresponding therapies.

Keywords: central nervous system disorders; mitochondrial dynamics; mitochondrial transport; mitophagy.

Figure 1

Three possible interplays of mitochondrial transport with mitochondrial quality control in axon. Mitochondria are distributed throughout the whole neuron, and neuronal soma is the main compartment where lysosomes residue and mitochondrial biogenesis takes place. Mitochondrial transport could mediate mitochondrial quality control through the following mechanisms: (A) mitochondria generated in soma are anterogradely transported into axon. Improved axonal mitochondrial quality could benefit from increased number of healthy mitochondria or probably mitochondrial fusion between healthy and damaged mitochondria. (B) Damaged mitochondria undergo retrograde transport for mitophagy in soma or fusing with somatic mitochondria. (C) Damaged mitochondrial mobility is arrested by PINK1/Parkin‐dependent degradation of Miro and cleared by local mitophagy in axon

Figure 2

Schematic representation of involvements of mitochondrial transport in neurodegeneration diseases. A, In intact neurons, mitochondrial transport system properly distributes mitochondria which satisfy energy demands of axons. Besides, damaged axonal mitochondria undergo autophagic clearance successfully in soma after retrograde transport. B, Mitochondrial transport is impaired in neurodegeneration diseases. Neurodegeneration‐related misfolded or mutant proteins can inhibit kinesin‐1 activity71, 73, 74, 103 and induce degradation of Miro1 in a Parkin‐dependent manner.89 The detailed mechanisms underlying the inhibition of mitochondrial anterograde transport in neurodegeneration need further investigations. Additionally, mitochondrial anchor protein syntaphilin buds out of axonal mitochondria and is further degraded in early stages of AD and fALS, which increased mitochondrial retrograde movements in axons.43 However, damaged mitochondria accumulate after returning back to soma due to autophagy defects and a lack of mitochondrial anterograde transport in a long run causes axonal energy depletion. C, The combination of corrected mitochondrial trafficking with autophagy activation might confer neuroprotection by degrading both somatic and axonal damaged mitochondria and ameliorating energy stress in axons simultaneously

Figure 3

Schematic representation of neuroprotection of mitochondrial anterograde transport against TAI. A, TAI causes mitochondrial damages and ATP depletion in injured axons of mature neurons in which syntaphilin expression is higher and mitochondrial mobility is limited. B, Increased mitochondrial anterograde transport by syntaphilin knockout56 or overexpression of Miro1,56, 122 DLK‐1,122 or Armcx157 replenishes axonal mitochondria and rescues energy collapse in injured axons, which further promotes axon regeneration. It is worth further investigations to treat TAI by enhancing mitochondrial anterograde transport with kinesin activators