Type I interferon potentiates metabolic dysfunction, inflammation, and accelerated aging in mtDNA mutator mice

Abstract

Mitochondrial dysfunction is a key driver of inflammatory responses in human disease. However, it remains unclear whether alterations in mitochondria-innate immune crosstalk contribute to the pathobiology of mitochondrial disorders and aging. Using the polymerase gamma (POLG) mutator model of mitochondrial DNA (mtDNA) instability, we report that aberrant activation of the type I interferon (IFN-I) innate immune axis potentiates immunometabolic dysfunction, reduces healthspan, 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 pro-inflammatory cytokine responses, and accelerates metabolic dysfunction. Ablation of IFN-I signaling attenuates hyper-inflammatory 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 diseases and aging.

Mitochondrial DNA Instability in Mammalian Cells

“…Various stresses such as mtDNA damage, defects in mtDNA maintenance factors ( 80 ), ROS, or microbial invasions ( 185 ) can result in the release of mtDNA into the cytosol, where it can come in contact with and trigger PRRs. The main route involved in the recognition of mtDNA in the cytosol is the cGAS-STING (stimulator of interferon genes) pathway, responsible for detecting the presence of invading DNA.…”

Mitochondrial Nucleic Acid as a Driver of Pathogenic Type I Interferon Induction in Mendelian Disease

“…upon loss of the mitochondrial proteases CLPP and YMEL1 ( 56 , 111 ). Similarly, multisystemic dysfunction caused by mtDNA mutation accumulation in the proofreading-deficient POLG mutator mouse can be rescued by ablation of cGAS-STING activity or IFN signaling ( 112 ). Whether maladaptive inflammation is observed in the corresponding human mitochondrial diseases has not been explored.…”

Necrosis drives susceptibility toMycobacterium tuberculosisin PolgD257Amutator mice

“…They are also frequently associated with chronic inflammation and autoimmunity. Type I interferonopathies, for example, are often caused by mutations that result in aberrant release of mitochondrial nucleic acids and chronic engagement of cytosolic nucleic acid sensing (3)(4)(5). Consistent with important links between mitochondrial health and immune function, patients with mitochondrial mutations are prone to frequent viral and bacterial infections that are often more severe (6)(7).…”

“…Although this mouse model does not harbor a specific human disease-associated mutation, it presents with symptoms that parallel many of the clinical manifestations seen in mitochondrial disease patients, such as cardiomyopathy, progressive hearing loss, and anemia (25). These mice also have exacerbated inflammatory responses and are susceptible to septic shock, which correlates with clinical symptoms seen in mitochondrial disease patients (3). Here, we report that POLG mtDNA mutator mice display enhanced susceptibility to Mtb infection evidenced by higher bacterial burdens, excessive neutrophil infiltration in the lung, and enhanced necrosis.…”