ATAD3A, the ATPase family AAA-domain containing protein 3A, is a nuclear-encoded mitochondrial membrane protein [2,5]. It belongs to the AAA-domain-containing ATPases superfamily and is crucial for maintaining mitochondrial DNA, structure, and function. ATAD3A is involved in multiple cellular processes such as mitochondrial dynamics, cell death, cholesterol metabolism, and protein translation [2,5]. It also plays a role in the mitochondria-endoplasmic reticulum connection and the regulation of mitophagy [1,4,6].

In Drosophila, overexpression of borR534W (homologous to the human c.1582C>T (p.Arg528Trp) variant in ATAD3A) led to decreased mitochondrial content, abnormal mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease in mitochondria, while overexpression of borWT resulted in larger, elongated mitochondria. Fibroblasts of an affected individual exhibited increased mitophagy, suggesting that the p.Arg528Trp variant functions through a dominant-negative mechanism, triggering mitophagy and reducing mitochondrial content [5]. In 5XFAD mouse models of Alzheimer's disease, ATAD3A oligomerization occurs, leading to cholesterol accumulation in mitochondria-associated ER membranes, APP processing, and synaptic loss. Suppressing ATAD3A oligomerization by heterozygous ATAD3A knockout restores neuronal CYP46A1 levels, normalizes brain cholesterol turnover, and reduces AD neuropathology and cognitive deficits [3].

In conclusion, ATAD3A is essential for mitochondrial function and dynamics. Studies using genetic models, such as Drosophila and mouse models, have revealed its role in various disease conditions. These models help to understand how ATAD3A mutations can lead to neurological syndromes like those seen in patients with ATAD3A-related disorders, and in Alzheimer's disease, highlighting its potential as a therapeutic target [3,5].

References:

1. Xie, Xiao-Qing, Yang, Yi, Wang, Qiang, Jin, Guoxiang, Bian, Xiu-Wu. 2023. Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria. In Cell research, 33, 215-228. doi:10.1038/s41422-022-00766-z. https://pubmed.ncbi.nlm.nih.gov/36627348/

2. Teng, Yong, Lang, Liwei, Shay, Chloe. . ATAD3A on the Path to Cancer. In Advances in experimental medicine and biology, 1134, 259-269. doi:10.1007/978-3-030-12668-1_14. https://pubmed.ncbi.nlm.nih.gov/30919342/

3. Zhao, Yuanyuan, Hu, Di, Wang, Rihua, Xu, Rong, Qi, Xin. 2022. ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer's disease models. In Nature communications, 13, 1121. doi:10.1038/s41467-022-28769-9. https://pubmed.ncbi.nlm.nih.gov/35236834/

4. Di Rienzo, Martina, Romagnoli, Alessandra, Ciccosanti, Fabiola, Piacentini, Mauro, Fimia, Gian Maria. 2021. AMBRA1 regulates mitophagy by interacting with ATAD3A and promoting PINK1 stability. In Autophagy, 18, 1752-1762. doi:10.1080/15548627.2021.1997052. https://pubmed.ncbi.nlm.nih.gov/34798798/

5. Harel, Tamar, Yoon, Wan Hee, Garone, Caterina, Bellen, Hugo J, Lupski, James R. 2016. Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes. In American journal of human genetics, 99, 831-845. doi:10.1016/j.ajhg.2016.08.007. https://pubmed.ncbi.nlm.nih.gov/27640307/

6. Li, Zeyu, Hu, Ou, Xu, Suowen, Lu, Jing, Liu, Peiqing. 2024. The SIRT3-ATAD3A axis regulates MAM dynamics and mitochondrial calcium homeostasis in cardiac hypertrophy. In International journal of biological sciences, 20, 831-847. doi:10.7150/ijbs.89253. https://pubmed.ncbi.nlm.nih.gov/38250153/