The Metabolism, Infection and Immunity Section (MINIS) studies the interplay between metabolism and the immune system through a translational research program involving patients with inborn errors of mitochondrial metabolism. The group studies two aspects of immunometabolism: 1) the effects of immune system activation on end-organ mitochondrial metabolism; and 2) the role of mitochondria in immune cell function.
Immune system activation and end-organ mitochondrial metabolism
The focus of the group's research on immune system activation and end-organ metabolism is based on the clinical observation that infection is a major cause of metabolic decompensation and associated morbidity and mortality in patients with mitochondrial disease. The MINIS uses animal models, combined with infectious organisms or immune activators, to yield insights into the metabolic perturbations seen in disorders of mitochondrial metabolism and to identify potential targets for intervention. Metabolic perturbations are demonstrated using metabolomics, mRNA profiling, proteomics, enzymology and in vivo metabolic imaging with MR spectroscopy.
Figure 1: The liver is a metabolic and immunologic organ. Signals such as cytokines, virus, PAMPs and DAMPs activate Kupffer cells in the liver. Interferons (e.g. IFNα) and inflammatory cytokines (e.g. IL-1, IL-6, TNFα) produced systemically or locally mediate changes in metabolic reserve and precipitate or exacerbate metabolic decompensation. Kupffer cell depletion studies have highlighted their role as a major node in this immune reaction
Role of mitochondria in immune cell function
Figure 2: Human mitochondrial morbidity map as a guide for identifying mitochondrial disease patients that may have defects in innate or adaptive immune responses. Cartoon provides a list of known mtDNA or nDNA-encoded mitochondrial disease-associated genes, and in which key mitochondrial function that gene product is known to play a role: (A) mitochondrial calcium transport, mitochondrial membrane (B) fission and (C) fusion, (D) mtDNA replication and stability, or (E) the respiratory chain. Genes listed were compiled from MitoMap.
The group also studies intermediary metabolism and immune cell function. Immune cells drastically alter their metabolic programming during activation and differentiation. The deficiencies present in patients with mitochondrial disease may affect these processes. In order to describe the interactions between intermediary metabolism and immune system function, the group developed a clinical protocol in the National Institutes of Health (NIH) Clinical Center, called the NIH MINI Study: Metabolism Infection and Immunity in IEM (NIH Clinical Trial NCT01780168).
This protocol is the first organized effort to examine immune function in patients with mitochondrial disease. These investigations are complemented by concurrent studies of immune function using animal models. By expanding the immune phenotype of patients with mitochondrial disease, these studies will have an impact on the clinical care of patients as well as serving as the foundation for understanding the role of mitochondria in immune function.
Tatiana Tarasenko, M.D., Ph.D., Staff Scientist
Project: Immune function in mitochondrial diseases due to nuclear mutations
Senta Kapnick, Ph.D., Post-doctoral Fellow
Project: The role of mtDNA variation in immune cell function
Russell D'Souza, Ph.D., Post-doctoral Fellow
Project: Metabolic decompensation and the central nervous system in mitochondrial diseases
Maxim Jestin, B.S., Post-baccalaureate Trainee
Project: Metabolic decompensation and mitochondrial hepatopathy
Ivan Yang, B.S., Post-baccalaureate Trainee
Project: Inflammation and the cell stress response in mitochondrial disease
Shannon Kruk, B.S.N., R.N., Research Nurse
Project: Clinical characterization of immunity in patients with mitochondrial disease
TBD: Staff Clinician
Last Updated: February 26, 2018