Diminished OPA1 expression and impaired mitochondrial morphology and homeostasis in Aprataxin-deficient cells

Nucleic Acids Res. 2019 May 7;47(8):4086-4110. doi: 10.1093/nar/gkz083.


Ataxia with oculomotor apraxia type 1 (AOA1) is an early onset progressive spinocerebellar ataxia caused by mutation in aprataxin (APTX). APTX removes 5'-AMP groups from DNA, a product of abortive ligation during DNA repair and replication. APTX deficiency has been suggested to compromise mitochondrial function; however, a detailed characterization of mitochondrial homeostasis in APTX-deficient cells is not available. Here, we show that cells lacking APTX undergo mitochondrial stress and display significant changes in the expression of the mitochondrial inner membrane fusion protein optic atrophy type 1, and components of the oxidative phosphorylation complexes. At the cellular level, APTX deficiency impairs mitochondrial morphology and network formation, and autophagic removal of damaged mitochondria by mitophagy. Thus, our results show that aberrant mitochondrial function is a key component of AOA1 pathology. This work corroborates the emerging evidence that impaired mitochondrial function is a characteristic of an increasing number of genetically diverse neurodegenerative disorders.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Transformed
  • Cell Line, Tumor
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics*
  • Electron Transport Chain Complex Proteins / genetics
  • Electron Transport Chain Complex Proteins / metabolism
  • GTP Phosphohydrolases / deficiency
  • GTP Phosphohydrolases / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Homeostasis / genetics
  • Humans
  • Lymphocytes / metabolism
  • Lymphocytes / pathology
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Mitophagy / genetics*
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics*
  • Oligonucleotide Array Sequence Analysis
  • Osteoblasts / metabolism
  • Osteoblasts / pathology
  • Oxidative Phosphorylation
  • Signal Transduction
  • Spinocerebellar Ataxias / congenital*
  • Spinocerebellar Ataxias / genetics
  • Spinocerebellar Ataxias / metabolism
  • Spinocerebellar Ataxias / pathology


  • APTX protein, human
  • DNA-Binding Proteins
  • Electron Transport Chain Complex Proteins
  • Nuclear Proteins
  • GTP Phosphohydrolases
  • OPA1 protein, human

Supplementary concepts

  • Spinocerebellar ataxia, autosomal recessive 1