Effects of OPA1 Mutations on Mitochondrial Morphology and Apoptosis: Relevance to ADOA Pathogenesis

J Cell Physiol. 2007 May;211(2):423-30. doi: 10.1002/jcp.20950.

Abstract

To characterize the molecular links between type-1 autosomal dominant optic atrophy (ADOA) and OPA1 dysfunctions, the effects of pathogenic alleles of this dynamin on mitochondrial morphology and apoptosis were analyzed, either in fibroblasts from affected individuals, or in HeLa cells transfected with similar mutants. The alleles were missense substitutions in the GTPase domain (OPA1(G300E) and OPA1(R290Q)) or deletion of the GTPase effector domain (OPA1(Delta58)). Fragmentation of mitochondria and apoptosis increased in OPA1(R290Q) fibroblasts and in OPA1(G300E) transfected HeLa cells. OPA1(Delta58) did not influence mitochondrial morphology, but increased the sensitivity to staurosporine of fibroblasts. In these cells, the amount of OPA1 protein was half of that in control fibroblasts. We conclude that GTPase mutants exert a dominant negative effect by competing with wild-type alleles to integrate into fusion-competent complexes, whereas C-terminal truncated alleles act by haplo-insufficiency. We present a model where antagonistic fusion and fission forces maintain the mitochondrial network, within morphological limits that are compatible with cellular functions. In the retinal ganglion cells (RGCs) of patients suffering from type-1 ADOA, OPA1-driven fusion cannot adequately oppose fission, thereby rendering them more sensitive to apoptotic stimuli and eventually leading to optic nerve degeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis* / drug effects
  • Apoptosis* / genetics
  • Blotting, Western
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism*
  • Gene Deletion
  • HeLa Cells
  • Humans
  • Microscopy, Fluorescence
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mutation*
  • Mutation, Missense
  • Optic Atrophy, Autosomal Dominant / genetics
  • Optic Atrophy, Autosomal Dominant / metabolism*
  • Optic Atrophy, Autosomal Dominant / pathology
  • Optic Atrophy, Autosomal Dominant / physiopathology
  • Phenotype
  • Skin / metabolism
  • Skin / pathology
  • Staurosporine / pharmacology
  • Transfection

Substances

  • GTP Phosphohydrolases
  • OPA1 protein, human
  • Staurosporine