Abstract
AIFM1 is a mitochondrial flavoprotein involved in caspase-independent cell death and regulation of respiratory chain complex biogenesis. Mutations in the AIFM1 gene have been associated with multiple clinical phenotypes, but the effectiveness of riboflavin treatment remains controversial. Furthermore, few studies explored the reasons underlying this controversy. We reported a 7-year-old boy with ataxia, sensorimotor neuropathy and muscle weakness. Genetic and histopathological analyses were conducted, along with assessments of mitochondrial function and apoptosis level induced by staurosporine. Riboflavin deficiency and supplementation experiments were performed using fibroblasts. A missense c.1019T > C (p. Met340Thr) variant of AIFM1 was detected in the proband, which caused reduced expression of AIFM1 protein and mitochondrial dysfunction as evidenced by downregulation of mitochondrial complex subunits, respiratory deficiency and collapse of ΔΨm. The proportion of apoptotic cells in mutant fibroblasts was lower than controls after induction of apoptosis. Riboflavin deficiency resulted in decreased AIFM1 protein levels, while supplementation with high concentrations of riboflavin partially increased AIFM1 protein levels in variant fibroblasts. In addition, mitochondrial respiratory function of mutant fibroblasts was partly improved after riboflavin supplementation. Our study elucidated the pathogenicity of the AIFM1 c.1019T > C variant and revealed mutant fibroblasts was intolerant to riboflavin deficiency. Riboflavin supplementation is helpful in maintaining the level of AIFM1 protein and mitochondrial respiratory function. Early riboflavin treatment may serve as a valuable attempt for patients with AIFM1 variant.
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Acknowledgements
This work was supported by the National Key Research and Development Program of China (No. 2021YFC2700904), National Natural Science Foundation of China (No. 82171394), Qingdao Technology Program for Health and Welfare (22-8-7-smjk-1-nsh) and the Taishan Scholars Program of Shandong Province.
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YZ performed experiments and drafted the manuscript. YL and HR modified the manuscript. BW, WW, JW and ZX obtained medical history and materials. FL obtained the fibroblasts. DZ finished muscle histopathological and immunohistochemical studies. CY revised the manuscript for intellectual content. KJ designed and conceptualized study.
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Supplementary file2 Figure S2. Representative images of TUNEL/DAPI staining of skin fibroblasts. Scale bar = 100 μm. (JPG 141 KB)
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Zhao, Y., Lin, Y., Wang, B. et al. A Missense Variant in AIFM1 Caused Mitochondrial Dysfunction and Intolerance to Riboflavin Deficiency. Neuromol Med 25, 489–500 (2023). https://doi.org/10.1007/s12017-023-08750-5
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DOI: https://doi.org/10.1007/s12017-023-08750-5