Broken Mitochondrial Gene Repair Triggers Immune System Overload
Scientists discovered that mutations in MTPAP, a gene that packages mitochondrial RNA, cause cells to leak double-stranded RNA into the cytoplasm, triggering excessive interferon production. This finding could explain autoimmune symptoms in rare genetic patients and opens a new pathway for understanding why mitochondrial diseases often involve chronic inflammation.
Originaltitel: Loss of MTPAP disrupts mitochondrial RNA processing causing upregulation of type I interferon signalling
Abstract Mitochondrial poly-A polymerase (MTPAP) is essential for mitochondrial mRNA (mt-mRNA) polyadenylation, a critical step in mt-mRNA maturation. Mutations in MTPAP have been reported to cause a mitochondrial cytopathy. Here, we provide evidence of enhanced type I interferon (IFN) signalling in the blood of patients carrying mutations in MTPAP . Further, deletion of MTPAP in a fibroblast cell model led to abnormalities in mitochondrial respiration and mtRNA processing, and an upregulation of type I IFN signalling. Notably, both in patients fibroblast and in MTPAP-deleted cells, we observed the accumulation of non-coding mtRNA and mitochondrial double-stranded RNA (mt-dsRNA) within enlarged mitochondrial RNA granules. Cytosolic release of mt-dsRNA led to type I IFN induction mediated primarily by the RNA sensor MDA5 and its adaptor MAVS. Our findings reveal a novel consequence of MTPAP dysfunction, highlighting how impaired mtRNA maturation can drive innate immune system activation.