Mechanical stress-induced release of mitochondrial double-stranded RNA activates RIG-I to drive osteogenic differentiation in aortic disease

Mechanical stretch in primary human aortic interstitial cells triggers a RIG-I/MDA5-dependent type I interferon and osteogenic program, promoting calcification via mitochondrial double-stranded RNA.

• Why it matters: Aortic valve stenosis involves early calcification, and RIG-I-like receptor gain-of-function is linked to interferonopathy with aortic calcification, leaving the mechanistic role unclear.
• What they did: Primary human aortic cells were treated with exogenous RIG-I and MDA5 agonists or exposed to mechanical stretch; CRISPR/Cas9 knockouts tested RIG-I/MDA5 or MAVS dependence, and mitochondrial RNA depletion tested RNA origin.
• The result: Stretch produced a predominant mitochondrial double-stranded RNA signal that was abolished by mitochondrial RNA depletion; ruxolitinib suppressed osteogenic factor expression in vitro and, in a murine wire-injury model, attenuated hemodynamic progression and improved survival.

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