Severe X-Linked Mitochondrial Encephalomyopathy Associated with a Mutation in Apoptosis-Inducing Factor

Abstract

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.

Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis

“…However, the effects may be tissue specific, since previous studies have observed a variable impact of AIF mutations on complex I activity (15,47), including the finding that decreasing AIF did not change complex I assembly, supercomplex formation, or activity. However, recently, a study (48) of two related patients with loss-offunction mutations in AIFM1, which affected both redox and DNA-binding properties of the AIF protein, showed no evidence of complex I deficiency in mitochondria taken from their skin fibroblasts or skeletal muscle biopsy samples.…”

AIF‐mediated caspase‐independent necroptosis: A new chance for targeted therapeutics

“…On the other hand, AIF deletion impairs the function of the respiratory chain via its role on maintaining mitochondrial morphology (8). Consequently, patients affected by a mitochondrial encephalopathy linked to an AIF mutation exhibit abnormal mitochondria (30).…”

Maternally inherited mitochondrial DNA disease in consanguineous families

“…2 All other proteins contributing to OXPHOS function are autosomally encoded, therefore defects can occur within nuclear or mitochondrial-encoded genes. Mitochondrial disease is genetically and clinically heterogeneous, and can follow mendelian or X-linked inheritance patterns, or be strictly matrilineal in the case of mtDNA mutations; [3][4][5] clinical presentations range from isolated organ involvement (deafness, diabetes and cardiomyopathy) to multisystem, syndromic presentations dominated by muscle and CNS involvement. 6,7 Such heterogeneity can mean that identifying the causative genetic defect is problematic.…”