Core Concepts
The ancestral p.W748S variant in the mitochondrial DNA replicase POLG1 compromises antiviral defense mechanisms, leading to variable disease manifestations in mitochondrial recessive ataxia syndrome (MIRAS) patients.
Abstract
The content discusses the role of the mitochondrial DNA replicase POLG1 in antiviral defense mechanisms and how a common European founder mutation, the p.W748S variant, can impact disease manifestation in mitochondrial recessive ataxia syndrome (MIRAS).
Key highlights:
Mitochondria play a critical role in antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments, which activate virus sensors and the type-I interferon (IFN-I) response.
MIRAS, caused by the POLG1 p.W748S variant, shows variable ages of onset and symptoms, suggesting the presence of unknown modifying factors.
The study found that POLG1 has a role in antiviral defense against double-stranded DNA and positive-strand RNA viruses, and the p.W748S variant dampens innate immune responses.
The p.W748S variant compromises mtDNA replisome stability, leading to mtDNA depletion, which is further aggravated by virus infection.
Low mtDNA and mtRNA release into the cytoplasm and a slow IFN response in MIRAS offer viruses an early replicative advantage, leading to an augmented pro-inflammatory response, neuronal loss, and liver inflammation and necrosis.
A population databank analysis showed an enrichment of immunodeficient traits in carriers of the POLG1 p.W748S mutation.
The findings suggest that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease, with important implications for the mitochondrial disease spectrum.
Stats
Patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages of onset and symptoms.
A population databank of around 300,000 Finnish individuals demonstrates enrichment of immunodeficient traits in carriers of the POLG1 p.W748S mutation.
Quotes
"Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection."
"Low mtDNA and mtRNA release into the cytoplasm and a slow IFN response in MIRAS offer viruses an early replicative advantage, leading to an augmented pro-inflammatory response, a subacute loss of GABAergic neurons and liver inflammation and necrosis."