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Elevated type I interferon responses potentiate metabolic dysfunction, inflammation, and accelerated aging in mtDNA
Yuanjiu Lei1, Camila Guerra Martinez1, Sylvia Torres-Odio1
1Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University, Bryan, TX, USA.
Abstract:
Mitochondrial dysfunction is a key driver of inflammatory responses in human disease. However, it remains unclear whether alterations in mitochondria-innate immune cross-talk contribute to the pathobiology of mitochondrial disorders and aging. Using the polymerase gamma (POLG) mutator model of mitochondrial DNA instability, we report that aberrant activation of the type I interferon (IFN-I) innate immune axis potentiates immunometabolic dysfunction, reduces health span, and accelerates aging in mutator mice. Mechanistically, elevated IFN-I signaling suppresses activation of nuclear factor erythroid 2-related factor 2 (NRF2), which increases oxidative stress, enhances proinflammatory cytokine responses, and accelerates metabolic dysfunction. Ablation of IFN-I signaling attenuates hyperinflammatory phenotypes by restoring NRF2 activity and reducing aerobic glycolysis, which combine to lessen cardiovascular and myeloid dysfunction in aged mutator mice. These findings further advance our knowledge of how mitochondrial dysfunction shapes innate immune responses and provide a framework for understanding mitochondria-driven immunopathology in POLG-related disorders and aging.
Insights
Mitochondrial dysfunction drives inflammation and aging. Blocking type I interferon (IFN-I) signaling restores protective pathways, improving health span in aging mice with mitochondrial DNA instability.
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.
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