The Mammalian-Specific Protein Armcx1 Regulates Mitochondrial Transport during Axon Regeneration

Abstract

Mitochondrial transport is crucial for neuronal and axonal physiology. However, whether and how it impacts neuronal injury responses, such as neuronal survival and axon regeneration, remain largely unknown. In an established mouse model with robust axon regeneration, we show that Armcx1, a mammalian-specific gene encoding a mitochondria-localized protein, is up-regulated after axotomy in this high regeneration condition. Armcx1 overexpression enhances mitochondrial transport in adult retinal ganglion cells (RGCs). Importantly, Armcx1 also promotes both neuronal survival and axon regeneration after injury, and these effects depend on its mitochondrial localization. Furthermore, Armcx1 knockdown undermines both neuronal survival and axon regeneration in the high regenerative capacity model, further supporting a key role of Armcx1 in regulating neuronal injury responses in the adult central nervous system (CNS). Our findings suggest that Armcx1 controls mitochondrial transport during neuronal repair.

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 .…”

“…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.…”

“…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.…”