Axotomy Induces Drp1-Dependent Fragmentation of Axonal Mitochondria

Frontiers in Molecular Neuroscience, 2021 · DOI: 10.3389/fnmol.2021.668670 · Published: June 3, 2021

Simple Explanation

This study investigates the role of axonal mitochondria in the axonal response to injury, specifically focusing on spinal cord injury (SCI). The primary features of mitochondrial dysfunction are the fragmentation of mitochondria through repeated bouts of fission into small submicron particles and the concurrent loss of the mitochondrial membrane potential resulting in ATP depletion and generation of ROS. Following spinal cord injury, there is a rapid fragmentation of mitochondria in corticospinal tract (CST) axons that persists for up to 3 days following injury before recovery of normal mitochondrial size begins, ultimately attaining sizes similar to uninjured axonal mitochondria 2 weeks after injury. The injury-induced mitochondrial fragmentation requires Drp1 and coincides with an increase in mitophagy that follows a temporal pattern similar to fragmentation. The study also found that mitochondrial calcium uptake is required for injury-induced mitochondrial fission, a finding supported by in vivo analysis of the role of mitochondria calcium uptake.

Study Duration

6 Weeks

Participants

Adult Sprague–Dawley rats

Evidence Level

Level 3; In vivo and in vitro experimental study

Key Findings

1
Spinal cord injury decreases the length of axonal mitochondria in CST neurons of adult Sprague–Dawley rats. At 2 h following injury, mitochondria closest to the site of injury exhibited decreased length.
2
Fragmentation of axonal mitochondria is associated with increased colocalization of mitochondria with mitophagy markers following spinal cord injury. At 2 h after injury, 18.5% of mitochondria were associated with localized increases in the levels of LC3
3
Inhibition of Drp1-mediated fission prevents injury-induced fragmentation of axonal mitochondria. mDivi-1 treatment decreased injury-induced mitochondrial fragmentation at 2 h and 1 day after injury.

Research Summary

This study used both in vitro and in vivo models to investigate the response of axonal mitochondria to axonal injury. Mitochondria within CST axons undergo rapid fragmentation following severing. Injury-induced mitochondrial shortening was also found in three different in vitro models of axonal injury. The observed fragmentation of axonal mitochondria following injury could severely reduce mitochondrial bioenergetics and impair growth from the cut axon tip. The study details the novel findings that following injury, axonal mitochondria of CST neurons undergo rapid fragmentation in a Drp1-dependent process. An axonal injury also results in an increase in mitophagy, indicating that the injury-induced mitochondrial fragments are dysfunctional.

Practical Implications

Therapeutic Strategies

New strategies aimed at axonal mitochondrial dynamics could prevent axonal dieback and promote axonal regeneration following injury.

Targeting Drp1

Inhibiting Drp1-mediated fission may be a viable therapeutic approach to prevent mitochondrial fragmentation and improve outcomes after spinal cord injury.

Mitochondrial Calcium Uptake

Targeting mitochondrial calcium uptake through MCU may provide another target for inhibiting injury-induced mitochondrial fragmentation and promoting axonal regeneration.

Study Limitations

1
The specific mechanisms by which mitochondrial calcium uptake regulates Drp1 activity remain unclear.
2
The study primarily focuses on CST axons; the response of mitochondria in other neuronal populations may differ.
3
Long-term effects of mDivi-1 treatment on axonal regeneration and functional recovery were not thoroughly investigated.

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