Metabolism, infection and immunity in inborn errors of mitochondrial metabolism

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

The overall goal of our translational research program is to understand the mechanisms involved in host-pathogen interactions in children with mitochondrial disease (MtD). Project 1: Infection and MtD This project focuses on understanding how mitochondrial dysfunction alters host–pathogen interactions during respiratory viral infection. By combining patient studies and mechanistic models with translational insights, we aim to identify pathways that explain why children with MtD experience severe outcomes from common viral infections. The characterization of patients with MtD continues via dedicated natural history studies, Metabolism, Infection and Immunity in Inborn Errors of Mitochondrial Metabolism (ClinicalTrials.gov Identifier: NCT01780168) and Acute infection in MtD (NCT04419870). Through these clinical protocols, we continue to accumulate natural history data that inform mechanistic studies aimed at improving clinical care during viral infection in children with MtD. This year, we reported that MtD leads to increased levels of sialic acid, the receptor for influenza virus. In the Ndufs4 knockout mouse model of complex I deficiency, this biochemical alteration enhanced viral binding, leading to higher viral loads and increased morbidity. Elevated sialic acid was also demonstrated on tissues from patients with MtD, extending out studies to the relationship between MtD and glycobiology. Importantly, these findings extend beyond MtD. Chronic respiratory diseases such as asthma and COPD, which also feature mitochondrial dysfunction, are marked by heightened risk of severe viral infections. Our study highlights a unifying mechanism in which impaired mitochondrial metabolism remodels the epithelial surface, increasing vulnerability to viral pathogens. Project 2: Mitochondrial Control of Immune Function This project focuses on how mitochondrial metabolism regulates immune cell activity, with an emphasis on adaptive immunity. Our goal is to define the metabolic requirements of T cells and other immune subsets, and to determine how mitochondrial dysfunction disrupts host defense. This year, we demonstrated that mitochondrial respiration through cytochrome c oxidase (Complex IV) is both necessary and sufficient for T cell function (Sci Adv, accepted). Using a mouse model of T cell–specific Complex IV deficiency, we showed that loss of this terminal respiratory step disrupted activation, proliferation, and effector responses. Restoration of Complex IV activity was sufficient to rescue these defects, providing definitive mechanistic evidence that adaptive immunity requires mitochondrial respiration at the level of Complex IV. This work establishes a direct and indispensable role for mitochondrial respiration in shaping T cell immunity, with implications for both mitochondrial disease and broader immunologic contexts. Clinical Relevance These discoveries have immediate translational significance: Predicting infection vulnerability: Elevated sialic acid expression provides a mechanistic explanation for why MtD patient suffer worse outcomes from viral respiratory infections. This insight opens the possibility of targeting sialic acid–related pathways or other host-directed mechanisms to reduce viral burden. Understanding immune dysfunction in MtD: The demonstration that Complex IV respiration is essential for T cell function helps explain why patients with MtD experience impaired immune responses during infection. It highlights mitochondrial integrity as a prerequisite for effective host defense. Broader applications: Beyond MtD, these mechanisms are relevant to chronic respiratory disease, immune dysfunction in general, and conditions where mitochondrial health shapes immune competence.