Cytochrome c oxidase dependent respiration is essential for T cell activation, proliferation and memory formation.

T cell activation, proliferation, and differentiation are fundamentally driven by shifts in cellular metabolism, with mitochondria playing a central role. Cytochrome c oxidase (COX, complex IV) is a key player in this process, as its activity is crucial for apoptosis, mtDNA maintenance, mitochondrial transcription, and mitochondrial respiration (MR), all of which influence T cell fate and function. Despite its known roles, the specific functions of COX required for T cell activity in vivo remain unclear.

Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease.

Mitochondrial diseases (MtD) represent a significant public health challenge due to their heterogenous clinical presentation, often severe and progressive symptoms, and the lack of effective therapies. Environmental exposures, such bacterial and viral infection, can further compromise mitochondrial function and exacerbate the progression of MtD. Infections in MtD patients more frequently progress to sepsis, pneumonia, and other detrimental inflammatory endpoints.

Primary oxidative phosphorylation defects lead to perturbations in the human B cell repertoire.

Introduction: The majority of studies on oxidative phosphorylation in immune cells have been performed in mouse models, necessitating human translation. To understand the impact of oxidative phosphorylation (OXPHOS) deficiency on human immunity, we studied children with primary mitochondrial disease (MtD).

Methods: scRNAseq analysis of peripheral blood mononuclear cells was performed on matched children with MtD (N = 4) and controls (N = 4).

Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.

Background: People with mitochondrial disease (MtD) are susceptible to metabolic decompensation and neurological symptom progression in response to an infection. Increasing evidence suggests that mitochondrial dysfunction may cause chronic inflammation, which may promote hyper-responsiveness to pathogens and neurodegeneration. We sought to examine transcriptional changes between MtD patients and healthy controls to identify common gene signatures of immune dysregulation in MtD.

Epitope-level profiling in children with mitochondrial disease reveals limitations in the antibacterial antibody repertoire.

Introduction: Immunometabolic studies in mice have suggested the importance of oxidative phosphorylation (OXPHOS) in humoral immunity. However, there are important distinctions between murine and human immunity. Furthermore, translational studies on the role of OXPHOS in humoral immunity are nearly absent from the biomedical literature.

Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.

People with mitochondrial disease (MtD) are susceptible to metabolic decompensation and neurological symptom progression in response to an infection. Increasing evidence suggests that mitochondrial dysfunction may cause chronic inflammation, which may promote hyperresponsiveness to pathogens and neurodegeneration. We collected whole blood from a cohort of MtD patients and healthy controls and performed RNAseq to examine transcriptomic differences.

Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory T cell differentiation in vitro.

Background: Modulation of metabolic flux through pyruvate dehydrogenase complex (PDC) plays an important role in T cell activation and differentiation. PDC sits at the transition between glycolysis and the tricarboxylic acid cycle and is a major producer of acetyl-CoA, marking it as a potential metabolic and epigenetic node.

Methods: To understand the role of pyruvate dehydrogenase complex in T cell differentiation, we generated mice deficient in T cell pyruvate dehydrogenase E1A () subunit using a CD4-cre recombinase-based strategy.

Adaptive immune responses to SARS-CoV-2 persist in the pharyngeal lymphoid tissue of children.

Most studies of adaptive immunity to SARS-CoV-2 infection focus on peripheral blood, which may not fully reflect immune responses at the site of infection. Using samples from 110 children undergoing tonsillectomy and adenoidectomy during the COVID-19 pandemic, we identified 24 samples with evidence of previous SARS-CoV-2 infection, including neutralizing antibodies in serum and SARS-CoV-2-specific germinal center and memory B cells in the tonsils and adenoids. Single-cell B cell receptor (BCR) sequencing indicated virus-specific BCRs were class-switched and somatically hypermutated, with overlapping clones in the two tissues.

Comprehensive profiling of the human viral exposome in households containing an at-risk child with mitochondrial disease during the 2020-2021 COVID-19 pandemic.

Background: Viral infection is a major cause of morbidity in children with mitochondrial disease (MtD). As a result, families with children with MtD are highly adherent to risk mitigation behaviours (RMBs) advised by the Centers for Disease Control and Prevention during the COVID-19 pandemic that can modulate infection risk.

Methods: Deep serologic phenotyping of viral infections was performed via home-based sampling by combining SARS-CoV-2 serologic testing and phage display immunoprecipitation and sequencing.

Short report: Vaccine attitudes in the age of COVID-19 for a population of children with mitochondrial disease.

Background: Children with developmental disabilities are vulnerable to morbidity associated with COVID-19.

Aims: To understand attitudes toward routine childhood vaccinations versus the COVID-19 vaccine in a population of families affected by mitochondrial disease (MtD), a form of developmental disability.

Methods And Procedures: An online survey was administered via several advocacy groups for children with MtD.

Leukocyte cytokine responses in adult patients with mitochondrial DNA defects.

Patients with oxidative phosphorylation (OxPhos) defects causing mitochondrial diseases appear particularly vulnerable to infections. Although OxPhos defects modulate cytokine production in vitro and in animal models, little is known about how circulating leukocytes of patients with inherited mitochondrial DNA (mtDNA) defects respond to acute immune challenges. In a small cohort of healthy controls (n = 21) and patients (n = 12) with either the m.

Undiagnosed COVID-19 in households with a child with mitochondrial disease.

Background: The impact of the COVID-19 pandemic on medically fragile populations, who are at higher risk of severe illness and sequelae, has not been well characterized. Viral infection is a major cause of morbidity in children with mitochondrial disease (MtD), and the COVID-19 pandemic represents an opportunity to study this vulnerable population.

Methods: A convenience sampling cross-sectional serology study was conducted (October 2020 to June 2021) in households (N = 20) containing a child with MtD (N = 22).

Risk mitigation behaviors to prevent infection in the mitochondrial disease community during the COVID-19 pandemic.

Background: A challenge during the COVID-19 pandemic has been widespread adherence to risk-reducing behaviors. Individuals with mitochondrial disease (MtD) are special population with an increased risk of morbidity associated with infection.

Purpose: To measure risk mitigation behaviors (RMBs) in families affected by MtD and identify factors that may influence these behaviors.

B cell receptor isotypes differentially associate with cell signaling, kinetics, and outcome in chronic lymphocytic leukemia.

In chronic lymphocytic leukemia (CLL), the B cell receptor (BCR) plays a critical role in disease development and progression, as indicated by the therapeutic efficacy of drugs blocking BCR signaling. However, the mechanism(s) underlying BCR responsiveness are not completely defined. Selective engagement of membrane IgM or IgD on CLL cells, each coexpressed by more than 90% of cases, leads to distinct signaling events.

PI3Kδ coordinates transcriptional, chromatin, and metabolic changes to promote effector CD8 T cells at the expense of central memory.

Patients with activated phosphatidylinositol 3-kinase delta (PI3Kδ) syndrome (APDS) present with sinopulmonary infections, lymphadenopathy, and cytomegalvirus (CMV) and/or Epstein-Barr virus (EBV) viremia, yet why patients fail to clear certain chronic viral infections remains incompletely understood. Using patient samples and a mouse model (Pik3cd mice), we demonstrate that, upon activation, Pik3cd CD8 T cells exhibit exaggerated features of effector populations both in vitro and after viral infection that are associated with increased Fas-mediated apoptosis due to sustained FoxO1 phosphorylation and Fasl derepression, enhanced mTORC1 and c-Myc signatures, metabolic perturbations, and an altered chromatin landscape. Conversely, Pik3cd CD8 cells fail to sustain expression of proteins critical for central memory, including TCF1.

Mitochondrial disease disrupts hepatic allostasis and lowers the threshold for immune-mediated liver toxicity.

Objective: In individuals with mitochondrial disease, respiratory viral infection can result in metabolic decompensation with mitochondrial hepatopathy. Here, we used a mouse model of liver-specific Complex IV deficiency to study hepatic allostasis during respiratory viral infection.

Methods: Mice with hepatic cytochrome c oxidase deficiency (LivCox10) were infected with aerosolized influenza, A/PR/8 (PR8), and euthanized on day five after infection following three days of symptoms.

Chemical individuality in T cells: A Garrodian view of immunometabolism.

Metabolically quiescent T cells circulate throughout the body in search of antigen. Following engagement of their cognate receptors, T cells undergo metabolic reprogramming to support their activation, differentiation, and ultimately function. In the spirit of Sir Archibald Garrod, this metabolic reprogramming actually imparts a chemical individuality which confers advantage, while in others confers vulnerability, depending upon the milieu.

AMP-activated protein kinase signaling regulated expression of urea cycle enzymes in response to changes in dietary protein intake.

Abundance of urea cycle enzymes in the liver is regulated by dietary protein intake. Although urea cycle enzyme levels rise in response to a high-protein (HP) diet, signaling networks that sense dietary protein intake and trigger changes in expression of urea cycle genes have not been identified. The aim of this study was to identify signaling pathway(s) that respond to changes in protein intake and regulate expression of urea cycle genes in mice and human hepatocytes.

Mitochondrial Dysfunction and the Aging Immune System.

Mitochondria are ancient organelles that have co-evolved with their cellular hosts, developing a mutually beneficial arrangement. In addition to making energy, mitochondria are multifaceted, being involved in heat production, calcium storage, apoptosis, cell signaling, biosynthesis, and aging. Many of these mitochondrial functions decline with age, and are the basis for many diseases of aging.

Macrophage derived TNFα promotes hepatic reprogramming to Warburg-like metabolism.

During infection, hepatocytes must undergo a reprioritization of metabolism, termed metabolic reprogramming. Hepatic metabolic reprogramming in response to infection begins within hours of infection, suggesting a mechanism closely linked to pathogen recognition. Following injection with polyinosinic:polycytidylic acid, a mimic of viral infection, a robust hepatic innate immune response could be seen involving the TNFα pathway at 2 h.

Etomoxir Actions on Regulatory and Memory T Cells Are Independent of Cpt1a-Mediated Fatty Acid Oxidation.

T cell subsets including effector (T), regulatory (T), and memory (T) cells are characterized by distinct metabolic profiles that influence their differentiation and function. Previous research suggests that engagement of long-chain fatty acid oxidation (LC-FAO) supports Foxp3 T cell and T cell survival. However, evidence for this is mostly based on inhibition of Cpt1a, the rate-limiting enzyme for LC-FAO, with the drug etomoxir.

Tissue acylcarnitine status in a mouse model of mitochondrial β-oxidation deficiency during metabolic decompensation due to influenza virus infection.

Despite judicious monitoring and care, patients with fatty acid oxidation disorders may experience metabolic decompensation due to infection which may result in rhabdomyolysis, cardiomyopathy, hypoglycemia and liver dysfunction and failure. Since clinical studies on metabolic decompensation are dangerous, we employed a preclinical model of metabolic decompensation due to infection. By infecting mice with mouse adapted influenza and using a pair-feeding strategy in a mouse model of long-chain fatty acid oxidation (Acadvl), our goals were to isolate the effects of infection on tissue acylcarnitines and determine how they relate to their plasma counterparts.

Fatty acid metabolism in CD8 T cell memory: Challenging current concepts.

CD8 T cells are key members of the adaptive immune response against infections and cancer. As we discuss in this review, these cells can present diverse metabolic requirements, which have been intensely studied during the past few years. Our current understanding suggests that aerobic glycolysis is a hallmark of activated CD8 T cells, while naive and memory (T ) cells often rely on oxidative phosphorylation, and thus mitochondrial metabolism is a crucial determinant of CD8 T cell development.