Mitochondrial Dynamics in Retinal Ganglion Cell Axon Regeneration and Growth Cone Guidance

Abstract

Failed axon regeneration and retinal ganglion cell (RGC) death after trauma or disease, including glaucomatous and mitochondrial optic neuropathies, are increasingly linked to mitochondrial dysfunction. Mitochondria are highly dynamic organelles whose size, organization, and function are regulated by a balance between mitochondrial fission and fusion. Mitochondria are ubiquitous in axonal growth cones both in vitro and in vivo and during development and regeneration. However, the roles that mitochondrial fission and fusion dynamics play in the growth cone during axon regeneration are largely unstudied. Here we discuss recent data suggesting mitochondria in the distal axon and growth cone play a central role in axon growth by integrating intrinsic axon growth states with signaling from extrinsic cues. Mitochondrial fission and fusion are intrinsically regulated in the distal axon in the growth cones of acutely purified embryonic and postnatal RGCs with differing intrinsic axon growth potentials. These differences in fission and fusion correlate with differences in mitochondrial bioenergetics; embryonic RGCs with high intrinsic axon growth potential rely more on glycolysis whereas RGCs with low intrinsic axon growth potential rely more on oxidative phosphorylation. Mitochondrial fission and fusion are also differentially modulated by KLFs that either promote or suppress intrinsic axon growth, and altering the balance between mitochondrial fission and fusion can differentially regulate axon growth rate and growth cone guidance responses to both inhibitory and permissive guidance cues. MitochondriaMitochondria integrate and modulate numerous cellular signaling pathways [32] and are increasingly recognized as central players in modulating signaling by both intrinsic and extrinsic factors that regulate neuronal survival and axon growth (Figure 1). Generally, mitochondria regulate neuronal growth, maintenance, and function by regulating basic metabolic functions, including ATP production through oxidative phosphorylation, calcium homeostasis, cellular apoptosis, lipid metabolism, and reactive oxygen species (ROS), nitric oxide (NO) and cyclic AMP (cAMP) signaling [33].