Afg3l2, an AFG3-like matrix AAA peptidase subunit 2, is a zinc metalloprotease and ATPase located in the inner mitochondrial membrane. It is involved in mitochondrial quality control of numerous nuclear-and mitochondrial-encoded proteins, playing a key role in proteostasis within mitochondria [1]. Mutations in Afg3l2 are associated with multiple neurological disorders, highlighting its biological importance in maintaining normal neurological function. Genetic models, such as KO mouse models, could potentially be valuable in further exploring its functions.

Mutations in Afg3l2 lead to a variety of neurological disorders. Biallelic mutations can cause autosomal recessive spastic ataxia-5 (SPAX5), characterized by early-onset cerebellar ataxia, spasticity, and progressive myoclonic epilepsy [5]. Dominant mutations are linked to autosomal dominant spinocerebellar ataxia type 28 (SCA28) [6]. Additionally, Afg3l2 mutations are a cause of optic neuropathy, including dominant optic atrophy (DOA), with DOA-associated mutations clustered in the ATPase domain [7]. Biochemically, Afg3l2 is responsible for degrading SLC25A39, a mitochondrial transporter for glutathione uptake, and its regulation is coupled with mitochondrial iron homeostasis [2,3]. Under normal conditions, it is tethered to prohibitin 1 (PHB1) to inhibit the opening of the mitochondrial permeability transition pore (mPTP), while down-regulation of PHB1 enhances its interaction with SPG7, leading to mPTP opening, mtDNA release, and inflammatory responses [4].

In conclusion, Afg3l2 is crucial for mitochondrial protein quality control, especially in relation to neurological functions. Model-based research, including potential KO mouse models, has revealed its significant roles in multiple neurological diseases like SCA28, SPAX5, and DOA. Understanding Afg3l2 functions can provide insights into the pathogenesis of these diseases, potentially leading to new diagnostic and therapeutic strategies.

References:

1. Ghosh Dastidar, Ranita, Banerjee, Saradindu, Lal, Piyush Behari, Ghosh Dastidar, Somasish. 2023. Multifaceted Roles of AFG3L2, a Mitochondrial ATPase in Relation to Neurological Disorders. In Molecular neurobiology, 61, 3788-3808. doi:10.1007/s12035-023-03768-z. https://pubmed.ncbi.nlm.nih.gov/38012514/

2. Shi, Xiaojian, DeCiucis, Marisa, Grabinska, Kariona A, Lam, Tukiet T, Shen, Hongying. 2023. Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis. In Molecular cell, 84, 802-810.e6. doi:10.1016/j.molcel.2023.12.008. https://pubmed.ncbi.nlm.nih.gov/38157846/

3. Liu, Yuyang, Liu, Shanshan, Tomar, Anju, Mansy, Sheref S, Birsoy, Kıvanç. 2023. Autoregulatory control of mitochondrial glutathione homeostasis. In Science (New York, N.Y.), 382, 820-828. doi:10.1126/science.adf4154. https://pubmed.ncbi.nlm.nih.gov/37917749/

4. Liu, Hao, Fan, Hualin, He, Pengcheng, Zhao, Guojun, Feng, Du. 2022. Prohibitin 1 regulates mtDNA release and downstream inflammatory responses. In The EMBO journal, 41, e111173. doi:10.15252/embj.2022111173. https://pubmed.ncbi.nlm.nih.gov/36245295/

5. Colucci, Fabiana, Neri, Marcella, Fortunato, Fernanda, Pugliatti, Maura, Sensi, Mariachiara. 2022. AFG3L2 Biallelic Mutation: Clinical Heterogeneity in Two Italian Patients. In Cerebellum (London, England), 22, 1313-1319. doi:10.1007/s12311-022-01497-y. https://pubmed.ncbi.nlm.nih.gov/36447112/

6. Chiang, Han-Lin, Fuh, Jong-Ling, Tsai, Yu-Shuen, Liao, Yi-Chu, Lee, Yi-Chung. 2021. Expanding the phenotype of AFG3L2 mutations: Late-onset autosomal recessive spinocerebellar ataxia. In Journal of the neurological sciences, 428, 117600. doi:10.1016/j.jns.2021.117600. https://pubmed.ncbi.nlm.nih.gov/34333379/

7. Caporali, Leonardo, Magri, Stefania, Legati, Andrea, Carelli, Valerio, Taroni, Franco. 2020. ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy. In Annals of neurology, 88, 18-32. doi:10.1002/ana.25723. https://pubmed.ncbi.nlm.nih.gov/32219868/