Antagonistic Interactions in Mitochondria ROS Signaling Responses to Manganese.

Antagonistic interaction refers to opposing beneficial and adverse signaling by a single agent. Understanding opposing signaling is important because pathologic outcomes can result from adverse causative agents or the failure of beneficial mechanisms. To test for opposing responses at a systems level, we used a transcriptome-metabolome-wide association study (TMWAS) with the rationale that metabolite changes provide a phenotypic readout of gene expression, and gene expression provides a phenotypic readout of signaling metabolites.

Study on the relationship between selenium and cadmium in diseased human lungs.

Cadmium (Cd) is a toxic environmental metal that interacts with selenium (Se) and contributes to many lung diseases. Humans have widespread exposures to Cd through diet and cigarette smoking, and studies in rodent models show that Se can protect against Cd toxicities. We sought to identify whether an antagonistic relationship existed between Se and Cd burdens and determine whether this relationship may associate with metabolic variation within human lungs.

Transcriptomic-Metabolomic Profiling in Mouse Lung Tissues Reveals Sex- and Strain-Based Differences.

Omics analyses are commonly used for identifying pathways and genes responsible for physiologic and pathologic processes. Though sex is considered a biological variable in rigorous assessments of pulmonary responses to oxidant exposures, the contribution of the murine strain is largely ignored. This study utilized an unbiased integrated assessment of high-resolution metabolomic profiling and RNA-sequencing to explore sex- and strain-dependent pathways in adult mouse lungs.

Microbial metabolite delta-valerobetaine is a diet-dependent obesogen.

Obesity and obesity-related metabolic disorders are linked to the intestinal microbiome. However, the causality of changes in the microbiome-host interaction affecting energy metabolism remains controversial. Here, we show the microbiome-derived metabolite δ-valerobetaine (VB) is a diet-dependent obesogen that is increased with phenotypic obesity and is correlated with visceral adipose tissue mass in humans.

Metabolites and metabolic pathways associated with glucocorticoid resistance in pregnant African-American women.

Glucocorticoid resistance (GR) is associated with exposure to chronic stress and an increased risk of metabolic and inflammatory disorders in both animal and human populations. Studies on ethnic disparities highlight the African-American (AA) population as having a high propensity to both GR and chronic stress exposure. Glucocorticoids and inflammation play a very important role in pregnancy outcome and fetal development.

MTOR-initiated metabolic switch and degeneration in the retinal pigment epithelium.

The retinal pigment epithelium (RPE) is a particularly vulnerable tissue to age-dependent degeneration. Over the life span, the RPE develops an expanded endo-lysosomal compartment to maintain the high efficiency of phagocytosis and degradation of photoreceptor outer segments (POS) necessary for photoreceptor survival. As the assembly and activation of the mechanistic target of rapamycin complex 1 (mTORC1) occur on the lysosome surface, increased lysosome mass with aging leads to higher mTORC1 activity.

Plasma high-resolution metabolomics identifies linoleic acid and linked metabolic pathways associated with bone mineral density.

Background & Aims: There is a considerable degree of variation in bone mineral density (BMD) within populations. Use of plasma metabolomics may provide insight into established and novel determinants of BMD variance, such as nutrition and gut microbiome composition, to inform future prevention and treatment strategies for loss of BMD. Using high-resolution metabolomics (HRM), we examined low-molecular weight plasma metabolites and nutrition-related metabolic pathways associated with BMD.

Early Pregnancy Serum Metabolite Profiles Associated with Hypertensive Disorders of Pregnancy in African American Women: A Pilot Study.

Hypertensive disorders of pregnancy (HDP) are the most common cardiometabolic complications of pregnancy, affecting nearly 10% of US pregnancies and contributing substantially to maternal and infant morbidity and mortality. In the US, women of African American race are at increased risk for HDP. Early biomarkers that reliably identify women at risk for HDP remain elusive, yet are essential for the early identification and targeting of interventions to improve maternal and infant outcomes.

Reductive Stress Causes Pathological Cardiac Remodeling and Diastolic Dysfunction.

Redox homeostasis is tightly controlled and regulates key cellular signaling pathways. The cell's antioxidant response provides a natural defense against oxidative stress, but excessive antioxidant generation leads to reductive stress (RS). This study elucidated how chronic RS, caused by constitutive activation of nuclear erythroid related factor-2 (caNrf2)-dependent antioxidant system, drives pathological myocardial remodeling.

Transcriptome Analysis Reveals Distinct Responses to Physiologic Toxic Manganese Exposure in Human Neuroblastoma Cells.

Manganese (Mn) is an essential trace element, which also causes neurotoxicity in exposed occupational workers. Mn causes mitochondrial toxicity; however, little is known about transcriptional responses discriminated by physiological and toxicological levels of Mn. Identification of such mechanisms could provide means to evaluate risk of Mn toxicity and also potential avenues to protect against adverse effects.

Environmental Cadmium Enhances Lung Injury by Respiratory Syncytial Virus Infection.

Cadmium (Cd) is a naturally occurring environmental toxicant that disrupts mitochondrial function at occupational exposure levels. The impacts of Cd exposure at low levels through dietary intake remain largely uncharacterized. Human respiratory syncytial virus (RSV) causes severe morbidity, which can require hospitalization and result in death in young children and elderly populations.

Low-dose cadmium potentiates lung inflammatory response to 2009 pandemic H1N1 influenza virus in mice.

Cadmium (Cd) is a toxic, pro-inflammatory metal ubiquitous in the diet that accumulates in body organs due to inefficient elimination. Responses to influenza virus infection are variable, particularly severity of pneumonia. We used a murine model of chronic low-dose oral exposure to Cd to test if increased lung tissue Cd worsened inflammation in response to sub-lethal H1N1 infection.

Metabolomic Responses to Manganese Dose in SH-SY5Y Human Neuroblastoma Cells.

Manganese (Mn)-associated neurotoxicity has been well recognized. However, Mn is also an essential nutrient to maintain physiological function. Our previous study of human neuroblastoma SH-SY5Y cells showed that Mn treatment comparable to physiological and toxicological concentrations in human brain resulted in different mitochondrial responses, yet cellular metabolic responses associated with such different outcomes remain uncharacterized.

Low-dose cadmium disrupts mitochondrial citric acid cycle and lipid metabolism in mouse lung.

Cadmium (Cd) causes acute and chronic lung toxicities at occupational exposure levels, yet the impacts of Cd exposure at low levels through dietary intake remain largely uncharacterized. Health concerns arise because humans do not have an effective Cd elimination mechanism, resulting in a long (10- to 35-y) biological half-life. Previous studies showed increased mitochondrial oxidative stress and cell death by Cd yet the details of mitochondrial alterations by low levels of Cd remain unexplored.

Selenium at the redox interface of the genome, metabolome and exposome.

Selenium (Se) is a redox-active environmental mineral that is converted to only a small number of metabolites and required for a relatively small number of mammalian enzymes. Despite this, dietary and environmental Se has extensive impact on every layer of omics space. This highlights a need for global network response structures to provide reference for targeted, hypothesis-driven Se research.

Putrescine as indicator of manganese neurotoxicity: Dose-response study in human SH-SY5Y cells.

Disrupted polyamine metabolism with elevated putrescine is associated with neuronal dysfunction. Manganese (Mn) is an essential nutrient that causes neurotoxicity in excess, but methods to evaluate biochemical responses to high Mn are limited. No information is available on dose-response effects of Mn on putrescine abundance and related polyamine metabolism.

Selenium supplementation prevents metabolic and transcriptomic responses to cadmium in mouse lung.

Background: The protective effect of selenium (Se) on cadmium (Cd) toxicity is well documented, but underlying mechanisms are unclear.

Methods: Male mice fed standard diet were given Cd (CdCl, 18 μmol/L) in drinking water with or without Se (NaSeO 20 μmol/L) for 16 weeks. Lungs were analyzed for Cd concentration, transcriptomics and metabolomics.

Mitochondrial network responses in oxidative physiology and disease.

Mitochondrial activities are linked directly or indirectly to all cellular functions in aerobic eukaryotes. Omics methods enable new approaches to study functional organization of mitochondria and their adaptive and maladaptive network responses to bioenergetic fuels, physiologic demands, environmental challenges and aging. In this review, we consider mitochondria collectively within a multicellular organism as a macroscale "mitochondriome", functioning to organize bioenergetics and metabolism as an organism utilizes environmental resources and protects against environmental threats.

Cadmium stimulates myofibroblast differentiation and mouse lung fibrosis.

Increasing evidence suggests that Cd at levels found in the human diet can cause oxidative stress and activate redox-sensitive transcription factors in inflammatory signaling. Following inflammation, tissue repair often involves activation of redox-sensitive transcription factors in fibroblasts. In lungs, epithelial barrier remodeling is required to restore gas exchange and barrier function, and aberrant myofibroblast differentiation leads to pulmonary fibrosis.

Redox dynamics of manganese as a mitochondrial life-death switch.

Sten Orrenius, M.D., Ph.

Metabolic pathways of lung inflammation revealed by high-resolution metabolomics (HRM) of H1N1 influenza virus infection in mice.

Influenza is a significant health concern worldwide. Viral infection induces local and systemic activation of the immune system causing attendant changes in metabolism. High-resolution metabolomics (HRM) uses advanced mass spectrometry and computational methods to measure thousands of metabolites inclusive of most metabolic pathways.

From the Cover: Manganese Stimulates Mitochondrial H2O2 Production in SH-SY5Y Human Neuroblastoma Cells Over Physiologic as well as Toxicologic Range.

Manganese (Mn) is an abundant redox-active metal with well-characterized mitochondrial accumulation and neurotoxicity due to excessive exposures. Mn is also an essential co-factor for the mitochondrial antioxidant protein, superoxide dismutase-2 (SOD2), and the range for adequate intake established by the Institute of Medicine Food and Nutrition Board is 20% of the interim guidance value for toxicity by the Agency for Toxic Substances and Disease Registry, leaving little margin for safety. To study toxic mechanisms over this critical dose range, we treated human neuroblastoma SH-SY5Y cells with a series of MnCl concentrations (from 0 to 100 μM) and measured cellular content to compare to human brain Mn content.

Lysine Acetylation Activates Mitochondrial Aconitase in the Heart.

High-throughput proteomics studies have identified several thousand acetylation sites on more than 1000 proteins. Mitochondrial aconitase, the Krebs cycle enzyme that converts citrate to isocitrate, has been identified in many of these reports. Acetylated mitochondrial aconitase has also been identified as a target for sirtuin 3 (SIRT3)-catalyzed deacetylation.

Redox regulation of insulin sensitivity due to enhanced fatty acid utilization in the mitochondria.

Obesity enhances the risk for the development of type 2 diabetes and cardiovascular disease. Loss in insulin sensitivity and diminished ability of muscle to take up and use glucose are characteristics of type 2 diabetes. Paradoxically, regulatory mechanisms that promote utilization of fatty acids appear to initiate diet-induced insulin insensitivity.