1. Academic Validation
  2. Elevated type I interferon responses potentiate metabolic dysfunction, inflammation, and accelerated aging in mtDNA mutator mice

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

  • Sci Adv. 2021 May 26;7(22):eabe7548. doi: 10.1126/sciadv.abe7548.
Yuanjiu Lei 1 Camila Guerra Martinez 1 Sylvia Torres-Odio 1 Samantha L Bell 1 Christine E Birdwell 1 Joshua D Bryant 1 Carl W Tong 2 Robert O Watson 1 Laura Ciaccia West 1 A Phillip West 3
Affiliations

Affiliations

  • 1 Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University, Bryan, TX, USA.
  • 2 Department of Medical Physiology, College of Medicine, Texas A&M University, Bryan, TX, USA.
  • 3 Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University, Bryan, TX, USA. awest@tamu.edu.
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.

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