scholarly journals Mitochondria-Related Nuclear Gene Expression in the Nucleus Accumbens and Blood Mitochondrial Copy Number After Developmental Fentanyl Exposure in Adolescent Male and Female C57BL/6 Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Cali A. Calarco ◽  
Megan E. Fox ◽  
Saskia Van Terheyden ◽  
Makeda D. Turner ◽  
Jason B. Alipio ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nucleus Accumbens ◽  
Mitochondrial Function ◽  
Copy Number ◽  
Drug Exposure ◽  
Related Gene ◽  
Developmental Exposure ◽  
Neuronal Signaling ◽  
Mitochondrial Copy Number ◽  
The Brain

The potency of the synthetic opioid fentanyl and its increased clinical availability has led to the rapid escalation of use in the general population, increased recreational exposure, and subsequently opioid-related overdoses. The wide-spread use of fentanyl has, consequently, increased the incidence of in utero exposure to the drug, but the long-term effects of this type of developmental exposure are not yet understood. Opioid use has also been linked to reduced mitochondrial copy number in blood in clinical populations, but the link between this peripheral biomarker and genetic or functional changes in reward-related brain circuitry is still unclear. Additionally, mitochondrial-related gene expression in reward-related brain regions has not been examined in the context of fentanyl exposure, despite the growing literature demonstrating drugs of abuse impact mitochondrial function, which subsequently impacts neuronal signaling. The current study uses exposure to fentanyl via dam access to fentanyl drinking water during gestation and lactation as a model for developmental drug exposure. This perinatal drug-exposure is sufficient to impact mitochondrial copy number in circulating blood leukocytes, as well as mitochondrial-related gene expression in the nucleus accumbens (NAc), a reward-related brain structure, in a sex-dependent manner in adolescent offspring. Specific NAc gene expression is correlated with both blood mitochondrial copy number and with anxiety related behaviors dependent on developmental exposure to fentanyl and sex. These data indicate that developmental fentanyl exposure impacts mitochondrial function in both the brain and body in ways that can impact neuronal signaling and may prime the brain for altered reward-related behavior in adolescence and later into adulthood.

scholarly journals Peripheral Insulin Regulates a Broad Network of Gene Expression in the Hypothalamus, Hippocampus and Nucleus Accumbens

2021 ◽  
Author(s):  
Weikang Cai ◽  
Xuemei Zhang ◽  
Thiago M. Batista ◽  
Rubén García-Martín ◽  
Samir Softic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nucleus Accumbens ◽  
Cholesterol Biosynthesis ◽  
Peripheral Circulation ◽  
Fatty Acyl ◽  
Pentose Phosphate ◽  
Gaba A ◽  
Expression Of Genes ◽  
Pentose Phosphate Pathways ◽  
The Brain

The brain is now recognized as an insulin sensitive tissue, however, the role of changing insulin concentrations in the peripheral circulation on gene expression in the brain is largely unknown. Here we perform hyperinsulinemic-euglycemic clamp on 3-month-old male C57BL/6 mice for 3 hours. We show that increases in peripheral insulin within the physiological range regulate expression of a broad network of gene expression in the brain compared with saline-infused controls. Insulin regulates distinct pathways in the hypothalamus, hippocampus and nucleus accumbens. Insulin shows its most robust effect in the hypothalamus and regulates multiple genes involved in neurotransmission, including up-regulating expression of multiple subunits of GABA-A receptors, Na<sup>+</sup> and K<sup>+</sup> channels, and SNARE proteins; differentially modulating glutamate receptors; and suppressing multiple neuropeptides. Insulin also strongly modulates metabolic genes in the hypothalamus, suppressing genes in the glycolysis and pentose phosphate pathways, while increasing expression of genes regulating pyruvate dehydrogenase and long-chain fatty acyl-CoA and cholesterol biosynthesis, thereby rerouting of carbon substrates from glucose metabolism to lipid metabolism required for the biogenesis of membranes for neuronal and glial function and synaptic remodeling. Furthermore, based on the transcriptional signatures, these changes in gene expression involve neurons, astrocytes, oligodendrocytes, microglia and endothelial cells. Thus, peripheral insulin acutely and potently regulates expression of a broad network of genes involved in neurotransmission and brain metabolism. Dysregulation of these pathways could have dramatic effects in normal physiology and diabetes.

scholarly journals Asthma and its relationship to mitochondrial copy number: Results from the Asthma Translational Genomics Collaborative (ATGC) of the Trans-Omics for Precision Medicine (TOPMed) program

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0242364
Author(s):  
Maxwell P. Cocco ◽  
Evan White ◽  
Shujie Xiao ◽  
Donglei Hu ◽  
Angel Mak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Precision Medicine ◽  
Copy Number ◽  
Sequence Data ◽  
Whole Genome Sequence ◽  
Mtdna Copy Number ◽  
Respiratory Complex ◽  
Mitochondrial Copy Number ◽  
Patient Reported ◽  
Asthma Status

Background Mitochondria support critical cellular functions, such as energy production through oxidative phosphorylation, regulation of reactive oxygen species, apoptosis, and calcium homeostasis. Objective Given the heightened level of cellular activity in patients with asthma, we sought to determine whether mitochondrial DNA (mtDNA) copy number measured in peripheral blood differed between individuals with and without asthma. Methods Whole genome sequence data was generated as part of the Trans-Omics for Precision Medicine (TOPMed) Program on participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) and the Study of African Americans, Asthma, Genes, & Environment II (SAGE II). We restricted our analysis to individuals who self-identified as African American (3,651 asthma cases and 1,344 controls). Mitochondrial copy number was estimated using the sequencing read depth ratio for the mitochondrial and nuclear genomes. Respiratory complex expression was assessed using RNA-sequencing. Results Average mitochondrial copy number was significantly higher among individuals with asthma when compared with controls (SAPPHIRE: 218.60 vs. 200.47, P<0.001; SAGE II: 235.99 vs. 223.07, P<0.001). Asthma status was significantly associated with mitochondrial copy number after accounting for potential explanatory variables, such as participant age, sex, leukocyte counts, and mitochondrial haplogroup. Despite the consistent relationship between asthma status and mitochondrial copy number, the latter was not associated with time-to-exacerbation or patient-reported asthma control. Mitochondrial respiratory complex gene expression was disproportionately lower in individuals with asthma when compared with individuals without asthma and other protein-encoding genes. Conclusions We observed a robust association between asthma and higher mitochondrial copy number. Asthma having an effect on mitochondria function was also supported by lower respiratory complex gene expression in this group.

scholarly journals Glycosylation-related gene expression profiling in the brain and spleen of scrapie-affected mouse

Glycobiology ◽  
2009 ◽  
Vol 19 (8) ◽  
pp. 879-889 ◽  
Author(s):  
F. Guillerme-Bosselut ◽  
L. Forestier ◽  
C. Jayat-Vignoles ◽  
J.-L. Vilotte ◽  
I. Popa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Related Gene ◽  
Affected Mouse ◽  
The Brain

Chemokine-related gene expression in the brain following ischemic stroke: No role for CXCR2 in outcome

2011 ◽  
Vol 1372 ◽  
pp. 169-179 ◽  
Author(s):  
Vanessa H. Brait ◽  
Jennifer Rivera ◽  
Brad R.S. Broughton ◽  
Seyoung Lee ◽  
Grant R. Drummond ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ischemic Stroke ◽  
Related Gene ◽  
The Brain

scholarly journals Peripheral Insulin Regulates a Broad Network of Gene Expression in the Hypothalamus, Hippocampus and Nucleus Accumbens

2021 ◽  
Author(s):  
Weikang Cai ◽  
Xuemei Zhang ◽  
Thiago M. Batista ◽  
Rubén García-Martín ◽  
Samir Softic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nucleus Accumbens ◽  
Cholesterol Biosynthesis ◽  
Peripheral Circulation ◽  
Fatty Acyl ◽  
Pentose Phosphate ◽  
Gaba A ◽  
Expression Of Genes ◽  
Pentose Phosphate Pathways ◽  
The Brain

The brain is now recognized as an insulin sensitive tissue, however, the role of changing insulin concentrations in the peripheral circulation on gene expression in the brain is largely unknown. Here we perform hyperinsulinemic-euglycemic clamp on 3-month-old male C57BL/6 mice for 3 hours. We show that increases in peripheral insulin within the physiological range regulate expression of a broad network of gene expression in the brain compared with saline-infused controls. Insulin regulates distinct pathways in the hypothalamus, hippocampus and nucleus accumbens. Insulin shows its most robust effect in the hypothalamus and regulates multiple genes involved in neurotransmission, including up-regulating expression of multiple subunits of GABA-A receptors, Na<sup>+</sup> and K<sup>+</sup> channels, and SNARE proteins; differentially modulating glutamate receptors; and suppressing multiple neuropeptides. Insulin also strongly modulates metabolic genes in the hypothalamus, suppressing genes in the glycolysis and pentose phosphate pathways, while increasing expression of genes regulating pyruvate dehydrogenase and long-chain fatty acyl-CoA and cholesterol biosynthesis, thereby rerouting of carbon substrates from glucose metabolism to lipid metabolism required for the biogenesis of membranes for neuronal and glial function and synaptic remodeling. Furthermore, based on the transcriptional signatures, these changes in gene expression involve neurons, astrocytes, oligodendrocytes, microglia and endothelial cells. Thus, peripheral insulin acutely and potently regulates expression of a broad network of genes involved in neurotransmission and brain metabolism. Dysregulation of these pathways could have dramatic effects in normal physiology and diabetes.

scholarly journals Yy1 Depletion in Pancreatic Beta Cells Leads to Energy Source Switch From Glycolysis to Oxidative Phosphorylation

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A327-A327
Author(s):  
Eliana M Perez-Garcia ◽  
Ruya Liu ◽  
Vijay K Yechoor
Keyword(s):  
Gene Expression ◽  
Energy Source ◽  
Copy Number ◽  
Mitochondrial Gene ◽  
Loss Of Function ◽  
Loop Formation ◽  
Β Cells ◽  
Mitochondrial Copy Number ◽  
Gene And Protein Expression ◽  
Insulinoma Cells

Abstract Background: Gene expression is determined by structural interactions in between transcription factors, cofactors and enhancer elements, as well as enhancer-promoter interactions (1). Both YY1 and CTCF are essential, zinc finger proteins that bind hypo-methylated DNA sequences, form homodimers, and thus facilitate DNA loop formation (1). ​However, YY1 preferentially occupies interacting enhancers and promoters, whereas CTCF preferentially occupies sites distal from these regulatory elements, forming larger loops and participating in insulation (1). A sequencing study of spontaneous functional insulinomas in a Chinese cohort identified a somatic a hotspot mutation in YY1 (c.C1115G/p.T372R) in 30% of the cases, associated with increased YY1 activity (2). YY1 is a critical transcription factor involved in the regulation of proliferation and metabolism (2). Hypothesis: YY1 loss-of-function alters energy source preference in pancreatic β-cells. Methods: YY1 stable loss-of-function in mouse insulinoma cell lines was achieved by shRNA lentiviral transduction. Mitochondrial membrane potential (MMP) was measured via flow cytometry of aggregated mitochondria to monomeric mitochondria ratio. Mitostress and complex-substrate controlled respiration were measured by Seahorse analyzer. Mitochondrial copy number was assessed by mitochondrial to nuclear DNA ratio. Quantitative qPCR and Western blotting were used to assess mitochondrial gene and protein expression. Results: Our data indicated that YY1 deficient β-cells showed increased MMP and maximal respiration. No significant differences were found in basal respiration, ATP production, proton leak, non-mitochondrial oxygen consumption or coupling efficiency. We also found that YY1 deficient β-cells exhibited reduced glycolytic capacity and decreased ETC complex IV activity, with concurrent increased complex I and II activity. In addition, YY1 deficient β-cells exhibited elevated mitochondrial copy number​ and increased quantitative mRNA of mitochondrial gene expression, which could be correlated with increased PGC1-α expression. Conclusions: YY1 is critical in the metabolic regulation of β-cells, particularly in the facilitation of glycolytic metabolism. YY1 activating mutations in functional spontaneous insulinoma cells can lead to a proliferation dysregulation accompanied by a metabolic switch that favors glycolysis, while the opposite occurs in YY1 deficient β-cells. References: (1) Weintraub AS et al, Cell 2017 Dec 14; 171:1573–1588 (2) Cao Y et al, Nat Commun 2013 Dec 10; 4:2810

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