Elevated type I interferon responses potentiate metabolic dysfunction, inflammation, and accelerated aging in mtDNA...

Area of Science:

• Immunology
• Mitochondrial Biology
• Aging Research

Background:

• Mitochondrial dysfunction is a known driver of inflammation in diseases.
• The role of mitochondria-innate immune crosstalk in aging and mitochondrial disorders is not fully understood.

Purpose of the Study:

• To investigate how mitochondria-innate immune crosstalk impacts aging and disease in a mouse model.
• To explore the therapeutic potential of modulating this crosstalk.

Main Methods:

• Utilized the polymerase gamma (POLG) mutator mouse model, which exhibits mitochondrial DNA instability.
• Analyzed the effects of type I interferon (IFN-I) signaling on immune responses, metabolism, and aging.
• Investigated the role of nuclear factor erythroid 2-related factor 2 (NRF2) and aerobic glycolysis.

Main Results:

• Aberrant type I interferon (IFN-I) activation accelerates aging and immunometabolic dysfunction in POLG mutator mice.
• IFN-I signaling suppresses NRF2, increasing oxidative stress and inflammation.
• Blocking IFN-I signaling restored NRF2 activity, reduced aerobic glycolysis, and attenuated inflammatory phenotypes, improving health span.

Conclusions:

• Mitochondria-innate immune crosstalk, particularly IFN-I signaling, significantly contributes to aging and immunopathology in mitochondrial disorders.
• Targeting IFN-I signaling offers a potential therapeutic strategy to mitigate aging-related diseases driven by mitochondrial dysfunction.