Defining how mitochondrial DNA stress regulates innate immune responses

• Published in: The Journal of immunology (1950) Vol. 200; no. 1_Supplement; pp. 169 - 169.14
• Main Authors: Martinez, Camila Guerra, Lei, Yuanjiu, West, Phillip
• Format: Journal Article
• Language: English
• Published: 01.05.2018
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.200.Supp.169.14

Abstract Polymerase gamma (pol γ) is nuclear-encoded protein responsible for mtDNA replication. POLG mutations are recognized as a significant cause of primary mitochondrial diseases and are implicated in a range of disorders. Several mouse models of POLG-related disease have been reported, the most well studied is the POLG-mutator mouse. Animals homozygous for the mutant alleles exhibit elevated mtDNA instability, and POLG-mutator mice exhibit pathology that mirrors various aspects of human POLG-related diseases. The literature has few descriptions about the immune system of POLG-mutator mice or patients with POLG-related disorders, despite the fact that aberrant immune responses have been implicated in the pathology of diseases with similar phenotypes. We have found that mitochondrial dysfunction, resulting from POLG mutation, alters innate immune responses at baseline and after challenge, which we hypothesize may exacerbate pathology in POLG-related mitochondrial disorders. To explore this hypothesis, we have stimulated macrophages from WT and POLG-mutator mice with various innate immune stimuli, and have uncovered that POLG-mutator macrophages display alterations in type I interferon responses, but strikingly, exhibit profound decreases in inflammasome-dependent interleukin-1 beta (IL-1b) secretion. Ongoing work will determine how mitochondrial dysfunction impairs inflammasome activation and IL-1b secretion in order to appreciate how aberrant innate immune responses influence POLG-related disease progression.