Missense Mutations Linked to Friedreich Ataxia Have Different but Synergistic Effects on Mitochondrial Frataxin Isoforms

Li, Hongqiao; Gakh, Oleksandr; Smith, Douglas Y.; Ranatunga, Wasantha; Isaya, Grazia

doi:10.1074/jbc.m112.435263

Cited by 27 publications

(41 citation statements)

References 45 publications

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“…All of these interactions are iron-independent (7,12,18). Complexes containing native oligomeric FXN , NFS1, and ISCU could be isolated upon fractionation of normal human cell extracts by size-exclusion chromatography followed by coimmunoprecipitation (7,19), underscoring the stability of these complexes. In contrast, native FXN was only recovered in fractions that contained no detectable NFS1 and only traces of ISCU (7,19 monomer.…”

mentioning

confidence: 84%

“…A Gly to Glu substitution may reduce the flexibility of the N-terminal portion of ISCU and may affect formation of hydrophobic interactions with NFS1. Finally, certain frataxin mutations identified in Friedreich ataxia patients are located in the ␤-sheet region of the protein and affect interactions of frataxin with other protein partners (52,65 to interact with NFS1 in vivo (19). In vitro, however, the W155R mutation affected the ability of both FXN and FXN to stimulate the cysteine desulfurase activity of NFS1 and to promote Fe-S cluster synthesis (19).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, native FXN was only recovered in fractions that contained no detectable NFS1 and only traces of ISCU (7,19 monomer. However, in both instances a large excess of FXN 81-210 monomer was required for complex formation (13,18), which may explain why this complex could not be detected under native conditions in human cells (7,19).…”

mentioning

confidence: 94%

“…Complexes containing native oligomeric FXN , NFS1, and ISCU could be isolated upon fractionation of normal human cell extracts by size-exclusion chromatography followed by coimmunoprecipitation (7,19), underscoring the stability of these complexes. In contrast, native FXN was only recovered in fractions that contained no detectable NFS1 and only traces of ISCU (7,19 monomer. However, in both instances a large excess of FXN 81-210 monomer was required for complex formation (13,18), which may explain why this complex could not be detected under native conditions in human cells (7,19).…”

mentioning

confidence: 99%

“…In the context of the complexes described above, both FXN and FXN 81-210 stimulate the cysteine desulfurase activity of [NFS1]⅐[ISD11] in the presence of ISCU and L-cysteine in vitro (12,19). Likewise, both isoforms support Fe-S cluster synthesis in the presence of [NFS1]⅐[ISD11], ISCU, L-cysteine, and ferrous iron under anaerobic conditions that prevent iron oxidation (7).…”

mentioning

confidence: 99%

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Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery

Gakh

Ranatunga

Smith

et al. 2016

Journal of Biological Chemistry

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confidence: 84%

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confidence: 99%

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confidence: 94%

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confidence: 99%

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confidence: 99%

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Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery

Gakh

Ranatunga

Smith

et al. 2016

Journal of Biological Chemistry

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Selected missense mutations impair frataxin processing in Friedreich ataxia

Clark

Butler

Isaacs

et al. 2017

Ann Clin Transl Neurol

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ObjectiveFrataxin (FXN) is a highly conserved mitochondrial protein. Reduced FXN levels cause Friedreich ataxia, a recessive neurodegenerative disease. Typical patients carry GAA repeat expansions on both alleles, while a subgroup of patients carry a missense mutation on one allele and a GAA repeat expansion on the other. Here, we report that selected disease‐related FXN missense mutations impair FXN localization, interaction with mitochondria processing peptidase, and processing.MethodsImmunocytochemical studies and subcellular fractionation were performed to study FXN import into the mitochondria and examine the mechanism by which mutations impair FXN processing. Coimmunoprecipitation was performed to study the interaction between FXN and mitochondrial processing peptidase. A proteasome inhibitor was used to model traditional therapeutic strategies. In addition, clinical profiles of subjects with and without point mutations were compared in a large natural history study.Results FXNI 154F and FXNG 130V missense mutations decrease FXN 81–210 levels compared with FXNWT, FXNR 165C, and FXNW 155R, but do not block its association with mitochondria. FXNI 154F and FXNG 130V also impair FXN maturation and enhance the binding between FXN 42–210 and mitochondria processing peptidase. Furthermore, blocking proteosomal degradation does not increase FXN 81–210 levels. Additionally, impaired FXN processing also occurs in fibroblasts from patients with FXNG 130V. Finally, clinical data from patients with FXNG 130V and FXNI 154F mutations demonstrates a lower severity compared with other individuals with Friedreich ataxia.InterpretationThese data suggest that the effects on processing associated with FXNG 130V and FXNI 154F mutations lead to higher levels of partially processed FXN, which may contribute to the milder clinical phenotypes in these patients.

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Phenotypic variation of FXN compound heterozygotes in a Friedreich ataxia cohort

Shen,

Rummey,

Lynch

2024

Ann Clin Transl Neurol

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ObjectiveMost individuals with Friedreich ataxia (FRDA) have homozygous GAA triplet repeat expansions in the FXN gene, correlating with a typical phenotype of ataxia and cardiomyopathy. A minority are compound heterozygotes carrying a GAA expansion on one allele and a mutation on the other. The study aim was to examine phenotypic variation among compound heterozygotes.MethodsData on FXN mutations were obtained from the Friedreich Ataxia Clinical Outcome Measures Study (FA‐COMS). We compared clinical features in a single‐site FA‐COMS cohort of 51 compound heterozygous and 358 homozygous patients, including quantitative measures of cardiac, neurologic, and visual disease progression.ResultsNon‐GAA repeat mutations were associated with reduced cardiac disease, and patients with minimal/no function mutations otherwise had a typical FRDA phenotype but with significantly more severe progression. The partial function mutation group was characterized by relative sparing of bulbar and upper limb function, as well as particularly low cardiac involvement. Other clinical features in this group, including optic atrophy and diabetes mellitus, varied widely depending on the specific type of partial function mutation.InterpretationThese data support that the typical FRDA phenotype is driven by frataxin deficiency, especially severe in compound heterozygotes with minimal/no function mutations, whereas the heterogeneous presentations of those with partial function mutations may indicate other contributing factors to FRDA pathogenesis.

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Missense Mutations Linked to Friedreich Ataxia Have Different but Synergistic Effects on Mitochondrial Frataxin Isoforms

Cited by 27 publications

References 45 publications

Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery

Architecture of the Human Mitochondrial Iron-Sulfur Cluster Assembly Machinery

Selected missense mutations impair frataxin processing in Friedreich ataxia

Phenotypic variation of FXN compound heterozygotes in a Friedreich ataxia cohort

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