Mitochondrial dysfunction as a central actor in intellectual disability-related diseases: an overview of Down syndrome, autism, Fragile X and Rett syndrome

Neurosci Biobehav Rev. 2014 Oct;46 Pt 2:202-17. doi: 10.1016/j.neubiorev.2014.01.012. Epub 2014 Feb 15.


Clinical manifestations typical of mitochondrial diseases are often present in various genetic syndromes associated with intellectual disability, a condition leading to deficit in cognitive functions and adaptive behaviors. Until now, the causative mechanism leading to intellectual disability is unknown and the progression of the condition is poorly understood. We first report latest advances on genetic and environmental regulation of mitochondrial function and its role in brain development. Starting from the structure, function and regulation of the oxidative phosphorylation apparatus, we review how mitochondrial biogenesis and dynamics play a central role in neurogenesis and neuroplasticity. We then discuss how dysfunctional mitochondria and alterations in reactive oxygen species homeostasis are potentially involved in the pathogenesis of various neurodevelopmental syndromes with a special focus on Down, Rett, Fragile X syndromes and autism spectrum disorders. Finally, we review and suggest novel therapeutic approaches aimed at improving intellectual disability by activating mitochondrial function and reducing oxidative stress to amiliorate the quality of life in the subjects affected.

Keywords: Autism; Down syndrome; Drug development; Epigallocatechine-3-gallate; Fragile X; Intellectual disability; Mitochondria; Mitochondrial dysfunction; Neurogenesis; Neuroplasticity; Oxidative phosphorylation; Oxidative stress; Rett syndrome.

Publication types

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

MeSH terms

  • Antioxidants / pharmacology
  • Antioxidants / therapeutic use
  • Autistic Disorder / complications
  • Autistic Disorder / metabolism
  • Autistic Disorder / physiopathology*
  • Down Syndrome / complications
  • Down Syndrome / metabolism
  • Down Syndrome / physiopathology*
  • Fragile X Syndrome / complications
  • Fragile X Syndrome / drug therapy
  • Fragile X Syndrome / metabolism
  • Fragile X Syndrome / physiopathology*
  • Humans
  • Intellectual Disability / complications
  • Intellectual Disability / metabolism
  • Intellectual Disability / physiopathology*
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Mitochondrial Diseases / complications
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Diseases / pathology
  • Mitochondrial Diseases / physiopathology*
  • Models, Biological
  • Molecular Targeted Therapy / methods
  • Neurogenesis / physiology
  • Neuronal Plasticity / physiology
  • Oxidative Phosphorylation
  • Oxidative Stress / drug effects
  • Rett Syndrome / complications
  • Rett Syndrome / metabolism
  • Rett Syndrome / physiopathology*


  • Antioxidants