ATAD1, also known as ATPase family AAA domain-containing 1, is a crucial protein in maintaining mitochondrial homeostasis. It belongs to the AAA protein family and, like its yeast ortholog Msp1, uses ATP hydrolysis to recognize and extract mislocalized membrane proteins from the outer mitochondrial membrane. This function is essential for mitochondrial protein quality control, preventing clogging of the mitochondrial translocase of the outer membrane (TOM) and allowing for the proper import of nuclear-encoded proteins into mitochondria. ATAD1 is also involved in regulating synaptic plasticity, mitochondrial fission-fusion dynamics, and the degradation of desmin intermediate filaments in muscle [1,2,4,6].

In human cells, knockout of ATAD1 leads to extensive accumulation of mitochondrial precursors, decreased protein import, and clogging of TOM, demonstrating its importance in mitochondrial protein import surveillance [2]. In neurons, ATAD1 deficiency disrupts the mitochondrial fission-fusion balance, causing mitochondrial fragmentation, and impairs dendritic branching, spine maturation, and glutamatergic synaptic transmission. Rescue experiments with an ATP hydrolysis-deficient mutant showed that synaptic deficits rely on ATAD1's ATP hydrolysis activity [5]. In hepatitis C virus (HCV) infection, ATAD1 knockout significantly enhances HCV infection, as ATAD1 normally interacts with the viral TA-protein NS5B and induces its proteasomal degradation [3].

In conclusion, ATAD1 is vital for maintaining mitochondrial function, regulating neurodevelopment, synaptic function, and antiviral defense. The use of gene knockout models, such as in human cells and neurons, has revealed its role in specific biological processes and disease-related conditions, providing insights into the underlying mechanisms and potential therapeutic targets for mitochondrial-related disorders, neurodegenerative diseases, and HCV-related pathologies.

References:

1. Wang, Lan, Walter, Peter. 2020. Msp1/ATAD1 in Protein Quality Control and Regulation of Synaptic Activities. In Annual review of cell and developmental biology, 36, 141-164. doi:10.1146/annurev-cellbio-031220-015840. https://pubmed.ncbi.nlm.nih.gov/32886535/

2. Kim, John, Goldstein, Madeleine, Zecchel, Lauren, Maxwell, Christopher A, Weidberg, Hilla. 2024. ATAD1 prevents clogging of TOM and damage caused by un-imported mitochondrial proteins. In Cell reports, 43, 114473. doi:10.1016/j.celrep.2024.114473. https://pubmed.ncbi.nlm.nih.gov/39024102/

3. Zhou, Qing, Yang, Yuhao, Xu, Zhanxue, Gao, Song, Li, Yi-Ping. 2023. ATAD1 inhibits hepatitis C virus infection by removing the viral TA-protein NS5B from mitochondria. In EMBO reports, 24, e56614. doi:10.15252/embr.202256614. https://pubmed.ncbi.nlm.nih.gov/37789674/

4. He, Jiajia, Liu, Ke, Wu, Yifan, Tang, Ai-Hui, Fu, Chuanhai. 2023. The AAA-ATPase Yta4/ATAD1 interacts with the mitochondrial divisome to inhibit mitochondrial fission. In PLoS biology, 21, e3002247. doi:10.1371/journal.pbio.3002247. https://pubmed.ncbi.nlm.nih.gov/37590302/

5. Yan, Hao-Hao, He, Jia-Jia, Fu, Chuanhai, Chen, Jia-Hui, Tang, Ai-Hui. 2024. ATAD1 Regulates Neuronal Development and Synapse Formation Through Tuning Mitochondrial Function. In International journal of molecular sciences, 26, . doi:10.3390/ijms26010044. https://pubmed.ncbi.nlm.nih.gov/39795902/

6. Aweida, Dina, Cohen, Shenhav. 2022. The AAA-ATPase ATAD1 and its partners promote degradation of desmin intermediate filaments in muscle. In EMBO reports, 23, e55175. doi:10.15252/embr.202255175. https://pubmed.ncbi.nlm.nih.gov/36278411/