Afg3l2, an AFG3-like matrix AAA peptidase subunit 2, is a zinc metalloprotease and an ATPase located in the inner mitochondrial membrane. It is involved in mitochondrial quality control of multiple nuclear-and mitochondrial-encoded proteins. It is associated with pathways related to proteostasis and mitochondrial glutathione homeostasis, and is of great biological importance in maintaining mitochondrial function [1,2,3].

Mutations in Afg3l2 lead to various neurological disorders. For example, dominant mutations can cause autosomal dominant spinocerebellar ataxia type 28 (SCA28), and biallelic mutations may result in spastic ataxia 5 (SPAX5) and optic atrophy type 12. In addition, it has been found that Afg3l2 is responsible for degrading the mitochondrial transporter SLC25A39, and this regulation is related to mitochondrial iron-sulfur cluster sensing and glutathione homeostasis [1,4,5,6]. In some studies, re-analysis of sequencing data has identified Afg3l2 variants associated with optic atrophy [7].

In conclusion, Afg3l2 plays a crucial role in mitochondrial quality control and is associated with multiple neurological disorders. The study of Afg3l2 mutations in different models helps to understand the pathogenesis of related diseases, providing a basis for diagnosis and potential treatment strategies.