ATAD3A Limits Aortic Dissection via Mito-Lysosome Contacts and Lipoylation

BACKGROUND: Aortic aneurysm and dissection (AAD) is a fatal vascular emergency with limited mechanism-based therapies. ATAD3A (ATPase family AAA [ATPases associated with diverse cellular activities] domain–containing protein 3A), a mitochondrial AAA + ATPase enriched at organelle contact sites, has been implicated in mitochondrial signaling, but its role in AAD remains unclear. METHODS: AAD was induced in wild-type, ATAD3A knock-in, and vascular smooth muscle cell (VSMC)–specific knockdown mice generated using short hairpin RNA against ATAD3A (sh-ATAD3A) by 3-week β-aminopropionitrile monofumarate intake or 28-day AngII (angiotensin II) infusion via osmotic minipumps. Aortic dilatation, dissection incidence, rupture-related mortality, and histology were assessed. Vascular smooth muscle cells were stimulated with AngII in vitro. Mitochondrial function was evaluated using Seahorse bioenergetics, membrane potential assay, and Ca 2 + imaging. ATAD3A–DLST (dihydrolipoamide S -succinyltransferase) interaction was examined by coimmunoprecipitation. Pharmacological modulation was performed with the copper chelator tetrathiomolybdate and the lipoylation inhibitor devimistat. RESULTS: ATAD3A expression was upregulated in human thoracic aortic dissection samples and in β-aminopropionitrile monofumarate–treated mouse aortas, with early downregulation then late upregulation in VSMCs. Systemic ATAD3A overexpression mitigated β-aminopropionitrile monofumarate–induced and AngII-induced aortic dilatation, reduced dilation incidence, and improved survival, whereas VSMC-specific knockdown accelerated vascular pathology. Mechanistically, ATAD3A overexpression reduced mitochondria-lysosome contacts, limited mitochondrial Ca 2 + influx, and suppressed the FDXR (ferredoxin reductase)/FDX1 (ferredoxin 1)/LIAS (lipoic acid synthetase) lipoylation pathway, decreasing DLST lipoylation and restraining cuproptosis, thereby preserving VSMC viability and delaying AAD progression. Pharmacological inhibition of cuproptosis using tetrathiomolybdate or Devimistat attenuated disease severity in vivo. CONCLUSIONS: ATAD3A protects against AAD by coordinating organelle contact and metabolic signaling to restrain mitochondrial Ca 2 + influx, NADPH flux, and DLST lipoylation-dependent cuproptosis in VSMCs. Targeting the ATAD3A-DLST-cuproptosis axis offers mechanistic insight and therapeutic potential for AAD.