Molecular Mechanisms behind Inherited Neurodegeneration of the Optic Nerve

Biomolecules. 2021 Mar 25;11(4):496. doi: 10.3390/biom11040496.


Inherited neurodegeneration of the optic nerve is a paradigm in neurology, as many forms of isolated or syndromic optic atrophy are encountered in clinical practice. The retinal ganglion cells originate the axons that form the optic nerve. They are particularly vulnerable to mitochondrial dysfunction, as they present a peculiar cellular architecture, with axons that are not myelinated for a long intra-retinal segment, thus, very energy dependent. The genetic landscape of causative mutations and genes greatly enlarged in the last decade, pointing to common pathways. These mostly imply mitochondrial dysfunction, which leads to a similar outcome in terms of neurodegeneration. We here critically review these pathways, which include (1) complex I-related oxidative phosphorylation (OXPHOS) dysfunction, (2) mitochondrial dynamics, and (3) endoplasmic reticulum-mitochondrial inter-organellar crosstalk. These major pathogenic mechanisms are in turn interconnected and represent the target for therapeutic strategies. Thus, their deep understanding is the basis to set and test new effective therapies, an urgent unmet need for these patients. New tools are now available to capture all interlinked mechanistic intricacies for the pathogenesis of optic nerve neurodegeneration, casting hope for innovative therapies to be rapidly transferred into the clinic and effectively cure inherited optic neuropathies.

Keywords: calcium handling; complex I; mitochondria-associated membranes; mitochondrial DNA; mitochondrial fission; mitochondrial fusion; optic atrophy; phospholipids; retinal ganglion cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • DNA, Mitochondrial / genetics
  • Electron Transport Complex I / genetics
  • Electron Transport Complex I / metabolism
  • Endoplasmic Reticulum / metabolism
  • Humans
  • Lipid Metabolism
  • Mitochondrial Dynamics
  • Optic Nerve / metabolism*
  • Optic Nerve Diseases / genetics
  • Optic Nerve Diseases / pathology*
  • Oxidative Phosphorylation
  • Reactive Oxygen Species / metabolism


  • DNA, Mitochondrial
  • Reactive Oxygen Species
  • Electron Transport Complex I