Mitochondria Localize to Injured Axons to Support Regeneration

Abstract

SUMMARY Axon regeneration is essential to restore the nervous system after axon injury. However, the neuronal cell biology that underlies axon regeneration is incompletely understood. Here we use in vivo single-neuron analysis to investigate the relationship between nerve injury, mitochondrial localization, and axon regeneration. Mitochondria translocate into injured axons, so that average mitochondria density increases after injury. Moreover, single-neuron analysis reveals that axons that fail to increase mitochondria have poor regeneration. Experimental alterations to axonal mitochondrial distribution or mitochondrial respiratory chain function result in corresponding changes to regeneration outcomes. Axonal mitochondria are specifically required for growth cone migration, identifying a key energy challenge for injured neurons. Finally, mitochondrial localization to the axon after injury is regulated in part by dual-leucine zipper kinase-1 (DLK-1), a conserved regulator of axon regeneration. These data identify regulation of axonal mitochondria as a new cell biological mechanism that helps determine the regenerative response of injured neurons.

Intrinsic mechanisms of neuronal axon regeneration

“…For example, ARMCX1 is a mammalian-specific gene that controls mitochondrial transport during neuronal repair 203 . Increased mitochondrial transport to injured axons is required for regeneration 203,204 , and CSPGs can prevent mitochondria from localizing to the growth cone 205 . There are also human-specific mRNA splice variants and human-specific genes in the nervous system that may play a role in the regenerative response 206–208 .…”

Mitostasis in Neurons: Maintaining Mitochondria in an Extended Cellular Architecture

“…Parallel work in invertebrate and rodent model organisms has shown that, on the one hand, mitochondria are likely to influence axonal growth patterns during development (Courchet et al, 2013; Spillane et al, 2013), but also after axotomy during regeneration (Cartoni et al, 2016; Han et al, 2016; Knowlton et al, 2017; Zhou et al, 2016). In this case, most data point towards a classical bioenergetic role, where axonal mitochondria at or near the growing axon tip are simply needed for sustained axon growth.…”

“…In this case, most data point towards a classical bioenergetic role, where axonal mitochondria at or near the growing axon tip are simply needed for sustained axon growth. Importantly, an axotomized neuron, ranging from C. elegans to mice, seems to endogenously upregulate the export of mitochondria into the axonal stump (Han et al, 2016; Misgeld et al, 2007). These observations underscore the evolutionary persistence even of higher order regulation of mitostatic processes, and opens the opportunity to use the power of genetic screens to understand the role of neuronal mitochondria in disease.…”

“…Disorders that more broadly affect axonal transport, such as tauopathies and SOD1 mutations, may include phenotypes with a significant mitochondrial etiology (De Vos et al, 2008; Millecamps and Julien, 2013). More recently changes in mitostatic processes also have been described during neuroinflammation (Sadeghian et al, 2016; Sorbara et al, 2014; Witte et al, 2014) and after neurotrauma (Cartoni et al, 2016; Han et al, 2016; Sheng, 2017; Zhou et al, 2016). Such links to pathology rightly spur interest in understanding mitostasis.…”

Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma

“…Depolarizing mitochondria does not increase the rate of Wallerian degeneration in superior cervical ganglion axons in vitro , indicating that degeneration-associated Ca ++ increases are extra-mitochondrial (Loreto et al, 2015). Axon regeneration, quite separate from degeneration, in mouse RGC axons (Cartoni et al, 2016) and C. elegans nerve cord axons (Han et al, 2016), does require mitochondria.…”