A stress-sensing C9ORF72-SMCR8 switch licenses FIP200 condensates for rapid mitophagy
Abstract
Acute mitochondrial damage demands rapid and spatially restricted quality control, yet how cells convert such stress into immediate mitophagic responses remains elusive. Here, we identify the C9ORF72-SMCR8 complex as a phosphorylation-gated molecular switch that couples mitochondrial damage to rapid mitophagy through regulated protein condensation. Ischemic stress induces transient upregulation of C9ORF72, which stabilizes SMCR8 and licenses its effector function. Upon mitochondrial damage, ULK1 phosphorylates SMCR8 at Ser471, enabling engagement with the FIP200 Claw domain and licensing FIP200 condensation at damaged mitochondria. These condensates nucleate mitophagosome biogenesis, thereby promoting rapid and spatially restricted mitochondrial clearance. Disruption of this switch impairs FIP200 condensation and exacerbates ischemic injury in vivo. Conversely, a minimal SMCR8-derived peptide is sufficient to reconstitute FIP200 condensate formation, restore mitophagy, and support tissue protection in vivo. Together, these findings define a phosphorylation-controlled condensate mechanism in which an intrinsically disordered region in SMCR8 couples mitochondrial stress to rapid mitophagy.
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