Advancements in AFG3L2 mutation and neurogenetic disorders: A comprehensive review

Neurogenetic disorders are a group of rare and diverse conditions characterized by significant genetic and clinical heterogeneity. Despite their prevalence, the etiology and pathogenic mechanisms of many of these disorders remain unclear, as effective treatments are lacking for the majority of cases. AFG3L2, encoded by a nuclear gene, plays a crucial role in mitochondrial function. It is transported to the inner mitochondrial membrane, where it functions as a subunit of the mitochondrial matrix AAA metalloprotease (m-AAA) complex. This complex is essential for protein quality control, as well as the processing and maturation of specific mitochondrial proteins. Mutations in the AFG3L2 gene have been implicated within various central nervous system degenerative disorders. Heterozygous mutations are associated with autosomal dominant spinocerebellar ataxia 28 (SCA28) and autosomal dominant optic atrophy (DOA), while homozygous mutations can lead to autosomal recessive spastic ataxia of Charlevoix-Saguenay (SPAX5). Interestingly, the specific variant sites in AFG3L2 associated with different diseases exhibit regional specificity. Variants linked to SCA28 and SPAX5 are predominantly found in the proteolytic domain of AFG3L2, whereas variants associated with DOA primarily cluster in the ATPase domain. In this review, we provide an overview of the structure and function of pathogenic mutations and pathological mechanisms of AFG3L2 in these inherited neurogenetic disorders.