Inborn Errors of Innate Immunity and Impaired Antimicrobial Defenses in Primary Mitochondrial Diseases Grant uri icon


  • PUBLIC ABSTRACT Mitochondrial diseases are a group of clinically variable disorders caused by the malfunction of cellular components called mitochondria, which are responsible for generating energy that powers vital body processes. Much of the research on mitochondrial disease has focused on the role of mitochondria in energy generation. However, recent studies from our lab and others have shown that mitochondria are key regulators of the immune system, orchestrating immune responses during viral or bacterial illness, as well as in non-infectious inflammatory diseases. Our Fiscal Year 2016 (FY19) Peer Reviewed Medical Research Program (PRMRP) Discovery Award tested the novel idea that mitochondrial dysfunction aberrantly engages the immune system, resulting in altered responses that exacerbate the pathology of mitochondrial disorders. Using the POLG-mutator mouse, a model of mitochondrial disease, subsequent experiments revealed elevated inflammatory and interferon responses in immune cells isolated from these animals; similar results were seen in immune cells taken from NDUFS4-deficient mice, a model of Leigh syndrome. Further study demonstrated that this aberrant immune signaling enhances tissue pathology and disease progression in POLG-mutator mice, highlighting novel roles of immune activation in the progression of mitochondrial disease. Patients with mitochondrial disease are more susceptible to infection by opportunistic bacteria or viral pathogens and also suffer elevated complications arising from these infections. The rate of sepsis in a recently studied cohort of patients with mitochondrial disease was markedly higher than the general population, and a study of 221 pediatric patients with mitochondrial disease highlighted that the two main causes of early death in these patients were sepsis and pneumonia. Although these findings suggest abnormal immunity, few studies have directly examined how immune dysfunction in mitochondrial disease impairs pathogen clearance leading to pneumonia, sepsis, and other complications. To address this gap in knowledge, our FY19 PRMRP Expansion proposal will directly examine the development, composition, and function of immune cells from the POLG-mutator and NDUFS4-deficient models of mitochondrial disease. These experiments will (1) define the prevalence of aberrant immune responses in mitochondrial diseases and (2) evaluate whether changes in the immune response as a result of mitochondrial disease impair viral and bacterial clearance causing sepsis and pneumonia in mouse models of disease. This research is innovative and clinically relevant in several ways. First, it will expand our previous work documenting aberrant immune responses into an additional models of mitochondrial disease. Second, there are presently no cures for many mitochondrial disorders and few treatments are available to slow the progression of these diseases. Moreover, it is unclear why patients with mitochondrial disease are more susceptible to recurrent infections and sepsis. This research will enhance our understanding of immune dysfunction in primary mitochondrial disorders and may lead to innovative treatments that alleviate inflammatory and infectious pathology in patients with these diseases.

date/time interval

  • 2018 - 2019