Severe X-linked mitochondrial encephalomyopathy associated with a mutation in apoptosis-inducing factor

Am J Hum Genet. 2010 Apr 9;86(4):639-49. doi: 10.1016/j.ajhg.2010.03.002. Epub 2010 Apr 1.


We investigated two male infant patients who were given a diagnosis of progressive mitochondrial encephalomyopathy on the basis of clinical, biochemical, and morphological features. These patients were born from monozygotic twin sisters and unrelated fathers, suggesting an X-linked trait. Fibroblasts from both showed reduction of respiratory chain (RC) cIII and cIV, but not of cI activities. We found a disease-segregating mutation in the X-linked AIFM1 gene, encoding the Apoptosis-Inducing Factor (AIF) mitochondrion-associated 1 precursor that deletes arginine 201 (R201 del). Under normal conditions, mature AIF is a FAD-dependent NADH oxidase of unknown function and is targeted to the mitochondrial intermembrane space (this form is called AIF(mit)). Upon apoptogenic stimuli, a soluble form (AIF(sol)) is released by proteolytic cleavage and migrates to the nucleus, where it induces "parthanatos," i.e., caspase-independent fragmentation of chromosomal DNA. In vitro, the AIF(R201 del) mutation decreases stability of both AIF(mit) and AIF(sol) and increases the AIF(sol) DNA binding affinity, a prerequisite for nuclear apoptosis. In AIF(R201 del) fibroblasts, staurosporine-induced parthanatos was markedly increased, whereas re-expression of AIF(wt) induced recovery of RC activities. Numerous TUNEL-positive, caspase 3-negative nuclei were visualized in patient #1's muscle, again indicating markedly increased parthanatos in the AIF(R201 del) critical tissues. We conclude that AIF(R201 del) is an unstable mutant variant associated with increased parthanatos-linked cell death. Our data suggest a role for AIF in RC integrity and mtDNA maintenance, at least in some tissues. Interestingly, riboflavin supplementation was associated with prolonged improvement of patient #1's neurological conditions, as well as correction of RC defects in mutant fibroblasts, suggesting that stabilization of the FAD binding in AIF(mit) is beneficial.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Inducing Factor / genetics*
  • Apoptosis Inducing Factor / metabolism
  • Apoptosis*
  • Caspase 3 / metabolism
  • Computer Simulation
  • DNA Primers / chemistry
  • DNA, Mitochondrial / genetics
  • DNA, Mitochondrial / metabolism
  • Dietary Supplements
  • Electron Transport / physiology
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Flavin-Adenine Dinucleotide / metabolism
  • Genes, X-Linked*
  • Humans
  • In Situ Nick-End Labeling
  • Infant, Newborn
  • Magnetic Resonance Imaging
  • Male
  • Mitochondrial Encephalomyopathies / genetics*
  • Mitochondrial Encephalomyopathies / metabolism
  • Mitochondrial Encephalomyopathies / pathology
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Mutation / genetics*
  • Nervous System Diseases / drug therapy
  • Nervous System Diseases / etiology
  • Pedigree
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Conformation
  • Riboflavin / administration & dosage
  • Staurosporine / pharmacology
  • Twins, Monozygotic


  • AIFM1 protein, human
  • Apoptosis Inducing Factor
  • DNA Primers
  • DNA, Mitochondrial
  • Flavin-Adenine Dinucleotide
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Caspase 3
  • Staurosporine
  • Riboflavin