ADA2 controls autophagy-dependent mitochondrial fitness to restrain type I interferon activation

Adenosine deaminase 2 (ADA2) is a secreted enzyme recently shown to localize to lysosomes and bind DNA, yet its cellular function remains elusive. ADA2 is highly expressed by innate immune cells, particularly macrophages, which are implicated in the inflammatory pathogenesis of ADA2 deficiency (DADA2). Accordingly, we investigated its function in macrophages and identified ADA2 as a key regulator of mitochondrial quality control. Transcriptomic profiling of patient monocytes revealed upregulation of nuclear-encoded mitochondrial genes, alongside stress-response and apoptotic programs. Consistently, ADA2-deficient macrophages exhibited increased mitochondrial mass, hyperpolarization, elevated mitochondrial ROS and ATP production, structural abnormalities in cristae, and defective mitophagy. These defects promoted mitochondrial DNA leakage via VDAC, triggering cytosolic DNA sensing, cGAS–STING activation, and hyperactive JAK–STAT–mediated IFN-I responses. Restoration of ADA2 partially rescued mitochondrial integrity and dampened IFN hyperactivation in macrophages and zebrafish. Together, our findings identify ADA2 as a key regulator of mitochondrial quality control that prevents organelle dysfunction and limits inflammation driven by aberrant IFN signaling.