Stimulation of hepatic mitochondrial calcium transport by elevated plasma insulin concentrations.
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ABSTRACT:
SUBMITTER: Dorman DM
PROVIDER: S-EPMC1165753 | biostudies-other | 1975 Sep
REPOSITORIES: biostudies-other
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Project description:IntroductionThe impact of hepatorenal function on plasma biomarkers of neuropathology is unknown. Herein, we measured several plasma biomarkers in patients with cirrhosis.MethodsPlasma phosphorylated tau (p-tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), total tau (t-tau), and ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) were measured in 135 adults with cirrhosis and 22 healthy controls using Simoa. Within cirrhosis, associations between biomarkers and hepatorenal function were explored using linear regression.Resultsp-tau181, NfL, t-tau, and UCHL1 were increased 2- to 4-fold in cirrhosis, whereas GFAP was not increased. Within cirrhosis, creatinine moderately correlated with p-tau181 (β = 0.75, P < .01), NfL (β = 0.32, P < .01), and t-tau (β = 0.31, P < .01), but not GFAP (β = -0.01, P = .88) or UCHL1 (β = -0.05, P = .60), whereas albumin showed weak, inverse correlations: p-tau181 (β = -0.18, P < .01), NfL (β = -0.22, P < .01), GFAP (β = -0.17, P < .05), t-tau (β = -0.20, P = .02), and UCHL1 (β = -0.15, P = .09).ConclusionsElevated p-tau181, NfL, and t-tau in cirrhosis were associated with renal impairment and hypoalbuminemia, suggesting that hepatorenal function may be important when interpreting plasma biomarkers of neuropathology.
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Project description:Intracellular calcium influences an array of pathways and affects cellular processes. With the rapidly progressing research investigating the molecular identity and the physiological roles of the mitochondrial calcium uniporter (MCU) complex, we now have the tools to understand the functions of mitochondrial Ca2+ in the regulation of pathophysiological processes. Herein, we describe the role of key MCU complex components in insulin resistance in mouse and human adipose tissue. Adipose tissue gene expression was analyzed from several models of obese and diabetic rodents and in 72 patients with obesity as well as in vitro insulin-resistant adipocytes. Genetic manipulation of MCU activity in 3T3-L1 adipocytes allowed the investigation of the role of mitochondrial calcium uptake. In insulin-resistant adipocytes, mitochondrial calcium uptake increased and several MCU components were upregulated. Similar results were observed in mouse and human visceral adipose tissue (VAT) during the progression of obesity and diabetes. Intriguingly, subcutaneous adipose tissue (SAT) was spared from overt MCU fluctuations. Furthermore, MCU expression returned to physiological levels in VAT of patients after weight loss by bariatric surgery. Genetic manipulation of mitochondrial calcium uptake in 3T3-L1 adipocytes demonstrated that changes in mitochondrial calcium concentration ([Ca2+]mt) can affect mitochondrial metabolism, including oxidative enzyme activity, mitochondrial respiration, membrane potential, and reactive oxygen species formation. Finally, our data suggest a strong relationship between [Ca2+]mt and the release of IL-6 and TNFα in adipocytes. Altered mitochondrial calcium flux in fat cells may play a role in obesity and diabetes and may be associated with the differential metabolic profiles of VAT and SAT.
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Project description:Purpose: To reveal the mechanism of mitochondrial DNA methylation in the progression of fatty liver and insulin resistance. Methods: Liver mitochondrial DNA bisulfite-sequencing of high-fat diet (HFD) and db/db diabetic mice were using Illumina 4000. Western blot, real-time PCR and confocal microscopy were used for further biochemical validation. Results: In the present study, we found increased mitochondrial localization of DNA methyltransferase 1 (DNMT1) in the liver of high-fat diet (HFD) and db/db diabetic mice. Whole genome bisulfite sequencing of mouse liver mtDNA revealed significant increase of cytosine methylation frequencies including CG, CHG and CHH on both L and H-strand in the diabetic mice comparing with normal control, and ND6 showed the most dramatic increase on the L-strand. Conclusions: Our present study suggests an epigenetic regulatory of mitochondrial homeostasis and insulin sensitivity by DNMT1, providing novel therapeutic targets for the prevention and treatment of fatty liver and type 2 diabetes.
2021-03-27 | GSE111996 | GEO
Project description:ObjectiveTransport of Ca2+ into pancreatic β cell mitochondria facilitates nutrient-mediated insulin secretion. However, the underlying mechanism is unclear. Recent establishment of the molecular identity of the mitochondrial Ca2+ uniporter (MCU) and associated proteins allows modification of mitochondrial Ca2+ transport in intact cells. We examined the consequences of deficiency of the accessory protein MICU2 in rat and human insulin-secreting cells and mouse islets.MethodssiRNA silencing of Micu2 in the INS-1 832/13 and EndoC-βH1 cell lines was performed; Micu2-/- mice were also studied. Insulin secretion and mechanistic analyses utilizing live confocal imaging to assess mitochondrial function and intracellular Ca2+ dynamics were performed.ResultsSilencing of Micu2 abrogated GSIS in the INS-1 832/13 and EndoC-βH1 cells. The Micu2-/- mice also displayed attenuated GSIS. Mitochondrial Ca2+ uptake declined in MICU2-deficient INS-1 832/13 and EndoC-βH1 cells in response to high glucose and high K+. MICU2 silencing in INS-1 832/13 cells, presumably through its effects on mitochondrial Ca2+ uptake, perturbed mitochondrial function illustrated by absent mitochondrial membrane hyperpolarization and lowering of the ATP/ADP ratio in response to elevated glucose. Despite the loss of mitochondrial Ca2+ uptake, cytosolic Ca2+ was lower in siMICU2-treated INS-1 832/13 cells in response to high K+. It was hypothesized that Ca2+ accumulated in the submembrane compartment in MICU2-deficient cells, resulting in desensitization of voltage-dependent Ca2+ channels, lowering total cytosolic Ca2+. Upon high K+ stimulation, MICU2-silenced cells showed higher and prolonged increases in submembrane Ca2+ levels.ConclusionsMICU2 plays a critical role in β cell mitochondrial Ca2+ uptake. β cell mitochondria sequestered Ca2+ from the submembrane compartment, preventing desensitization of voltage-dependent Ca2+ channels and facilitating GSIS.
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