Innate Immune Signaling and Type I Interferon Responses as Novel Modifiers of Mitochondrial Disease Pathology
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Background and Rationale: Mitochondrial diseases are a group of clinically heterogeneous disorders caused by mitochondrial malfunction. These diseases often result from mutations in genes that function in oxidative phosphorylation and mitochondrial metabolism, but may also be caused by defects in mitochondrial DNA (mtDNA) replication or nucleotide metabolism. Mutations in the POLG gene, which encodes the catalytic subunit of human mtDNA polymerase gamma, lead to mtDNA instability (i.e., depletion, mutation, and deletion) and are recognized as a major cause of primary mitochondrial syndromes. These so-called POLG-related disorders include Alpers-Huttenlocher syndrome, ataxia neuropathy spectrum, and progressive external ophthalmoplegia, all of which are characterized by multiple-organ pathology with varying degrees of nervous, muscular, digestive, and endocrine system involvement. Although the molecular genetic causes of POLG-related mitochondrial diseases are increasingly well understood, the underlying mechanisms that cause pathology, as well as clinical variability, are less clear. Much of the mechanistic research into these disorders has focused on the metabolic and energetic alterations that cause cell and tissue dysfunction; however, as mitochondria are integrated into many cellular pathways, this approach has likely overlooked other important networks that may contribute to disease pathology. For example, a rapidly expanding body of literature indicates that mitochondria are key regulators of the mammalian innate immune response. Mitochondria serve as antiviral signaling hubs and facilitate antibacterial immunity, but they can also promote inflammation following cell and tissue stress. In agreement with the latter, recent work has demonstrated that mtDNA instability potently engages the innate immune system, triggering the production of proinflammatory mediators and type I interferons (IFN-I).Hypothesis: Unresolved IFN-I and inflammatory responses have been implicated in a number of diverse pathologies, some of which are present in the multi-organ disease of patients afflicted with POLG-related disorders. We will therefore explore the novel hypothesis that mtDNA instability resulting from POLG mutation aberrantly engages nucleic acid sensors of the innate immune system, resulting in IFN-I and proinflammatory responses that exacerbate the pathology of POLG-related mitochondrial disorders.Study Design and Expected Results: The POLG-mutator mouse model of mitochondrial disease, which exhibits disrupted exonuclease function and elevated mtDNA instability, presents with age-related pathology that mirrors various aspects of human POLG-related disease, including cardiomyopathy, sensorineural hearing loss, and ovarian/testicular failure. Our first objective is to characterize IFN-I and proinflammatory responses throughout the progression of disease in POLG-mutator mice. We will employ transcriptomics, gene expression profiling, protein/cytokine analysis, immunohistochemistry, and flow cytometry to characterize these signatures in multiple affected tissues of POLG-mutator cohorts. Next, we will employ a genetic approach to develop POLG-mutator mice with deficiencies in key innate immune signaling pathways. We will utilize these double mutant animals to determine whether the absence of cGAS, STING, and IFN-I signaling attenuates mitochondrial dysfunction, tissue pathology, and premature aging phenotypes in POLG-mutator mice. Based upon preliminary data and bioinformatic analyses, we expect to document progressively increasing IFN-I and inflammatory responses in the tissues of POLG-mutator animals, and we predict that that inhibition of innate immune signaling cascades will slow or alleviate pathology in this mouse model of mitochondrial disease.Innovation and Future Implications:This project constitutes the first systematic investigation into the contributions of innate immune signaling to the progression of a murine model of POLG-related mitochondrial disease.This proposal will explore the novel hypothesis that hyper-stimulation of IFN-I and proinflammatory responses further exacerbate mitochondrial dysfunction and multi-organ pathology in POLG-related diseases. The results obtained will provide a robust foundation for future research that focuses on immune pathology of mitochondrial diseases in other mouse models and clinical settings.Presently, there are no cures for POLG-related disorders, and few treatments are available to slow the progression of these diseases. This research may lay the foundation for studies exploring the therapeutic targeting of inflammatory and IFN-I pathways as a means to attenuate multi-system pathology of POLG-related disorders and other primary mtDNA diseases.
