Mechanism Description

ATAD3A (ATPase family AAA-domain containing protein 3A) is an AAA-ATPase located at mitochondrial contact sites, where it spans the inner and outer membranes with its N-terminal domain in the cytosol and C-terminal domain in the matrix. It governs mitochondrial dynamics, maintains mtDNA stability, and regulates cholesterol metabolism and trafficking. Under neurological disease pathologies, ATAD3A forms oligomers and recruits the fission GTPase Drp1 to the mitochondria. This interaction induces Drp1-mediated mitochondrial fragmentation, impairs TFAM-related mtDNA maintenance leading to mtDNA depletion, and disrupts CYP46A1-dependent brain cholesterol turnover, ultimately driving bioenergetic defects and neurodegeneration.

JQ-A1 is a cell-penetrating decoy peptide that contains a sequence homologous to the coiled-coil domain of ATAD3A. By directly binding to ATAD3A at this site, JQ-A1 acts as a competitive decoy to block Drp1 recruitment and suppress aberrant ATAD3A oligomerization. In Alzheimer's disease (AD) mouse models, treatment with JQ-A1 inhibits ATAD3A oligomerization, attenuating excessive mitochondrial fission, mtDNA loss, and bioenergetic impairment. It attenuates Aβ load, reduces GFAP- and Iba1-mediated neuroinflammation (gliosis), and restores CYP46A1 levels to correct excessive brain cholesterol accumulation. Additionally, it preserves synaptic integrity and improves short- and long-term spatial memory without impacting wild-type mice.