Atad3a, an ATPase family AAA-domain containing protein 3A, is a nuclear-encoded mitochondrial membrane protein [3,6]. It is a member of the AAA-domain-containing ATPases superfamily and is crucial for maintaining mitochondrial DNA, structure, and function. Atad3a is involved in diverse cellular processes such as mitochondrial dynamics, cell death, cholesterol metabolism, and protein translation [3,6]. It also plays a role in the mitochondria-endoplasmic reticulum connection and is associated with multiple pathways including mitophagy, cholesterol mitochondrial trafficking, and the regulation of interferon signaling [1,2,3,5].

In Drosophila, overexpression of borR534W, homologous to the human c.1582C>T (p.Arg528Trp) variant in Atad3a, led to decreased mitochondrial content, abnormal morphology, and increased autophagy, while homozygous null bor larvae showed a significant decrease in mitochondria, and overexpression of borWT resulted in larger, elongated mitochondria [6]. In 5XFAD mouse models of Alzheimer's disease, ATAD3A oligomerization at the mitochondria-associated ER membranes led to cholesterol accumulation, APP processing, and synaptic loss, and suppressing ATAD3A oligomerization restored normal brain cholesterol turnover and reduced neuropathology and cognitive deficits [4]. In triple-negative breast cancer, paclitaxel increased ATAD3A expression, disrupting PD-L1 proteostasis by restraining PINK1-dependent mitophagy, and targeting ATAD3A could reset the antitumor immune microenvironment and increase the efficacy of chemoimmunotherapy [2].

In conclusion, Atad3a is essential for mitochondrial function and dynamics. Studies using genetic models like Drosophila and mouse models have revealed its role in various disease conditions such as neurological syndromes, Alzheimer's disease, and breast cancer. These models have provided insights into how Atad3a mutations or dysregulation can lead to disruptions in cellular processes, highlighting its potential as a therapeutic target in these diseases.