Mechanisms of Innate Immune Activation in Mitochondrial Disease Onset and Progression

Project summary/abstract Genetic mitochondrial diseases (GMD) are the most common cause of inherited metabolic disorders and among the most common causes of inherited neurological disease. They are characterized by defects in mitochondrial function and impact over 1 in 4,000 individuals. This genetically and clinically diverse group of diseases can affect many organ systems. Neurological consequences are common. The mechanisms underlying GMD pathogenesis are poorly understood, and there are currently no proven therapies for any GMD. An understanding of the pathogenesis of GMD is critically needed to develop effective strategies for clinical intervention. Intriguing new published and unpublished findings from our group and others reveals that the innate immune system plays a critical causal role in the pathogenesis of at least certain forms of GMD. The overarching goal of this proposal is to elucidate the mechanisms underlying immune activation and recruitment in Leigh syndrome (LS), the most common form of pediatric GMD. LS is universally fatal with severe neurological disease, including cerebellar ataxia, seizures, hypotonia, lactic acidosis, and progressive, symmetric necrotizing lesions in the brainstem and cerebellum. We have recently demonstrated that cells of the innate immune system drive disease in LS. This proposal seeks to investigate the mechanisms underlying innate immune activation, which drives disease downstream of mitochondrial dysfunction, in the Ndufs4 knockout (KO) mouse model of LS. We hypothesize that a discrete process underlies immune activation and the formation of neurodegenerative lesions in the Ndufs4(KO) mouse. We further hypothesize that innate immune-activating mitochondrial macromolecules mediate neuroinflammatory disease in LS. We will use single cell RNA seq, flow cytometry, immunohistochemistry, genetic mouse models and antibody-based depletion of specific immune components to characterize the immune milieu of CNS lesions in the Ndufs4(KO) mouse throughout the disease process and investigate the possibility of monitoring disease progression by tracking circulating inflammatory factors. The studies proposed here will advanced our understanding of the pathogenesis of LS and reveal new opportunities for therapeutic intervention in LS, and possibly other forms of GMD. In addition to illuminating underlying mechanisms of LS and GMD pathogenesis, the findings from this research will inform investigation into the disease processes of other conditions with underlying components of mitochondrial dysfunction and immune involvement, such as multiple sclerosis.