To examine the roles of mitochondrial calcium Ca ([Ca]) and cytosolic Ca ([Ca]) in the regulation of hepatic mitochondrial fat oxidation, we studied a liver-specific mitochondrial calcium uniporter knockout (MCU KO) mouse model with reduced [Ca] and increased [Ca] content. Despite decreased [Ca], deletion of hepatic MCU increased rates of isocitrate dehydrogenase flux, α-ketoglutarate dehydrogenase flux, and succinate dehydrogenase flux in vivo. Rates of [C]palmitate oxidation and intrahepatic lipolysis were increased in MCU KO liver slices, which led to decreased hepatic triacylglycerol content. These effects were recapitulated with activation of CAMKII and abrogated with CAMKII knockdown, demonstrating that [Ca] activation of CAMKII may be the primary mechanism by which MCU deletion promotes increased hepatic mitochondrial oxidation. Together, these data demonstrate that hepatic mitochondrial oxidation can be dissociated from [Ca] and reveal a key role for [Ca] in the regulation of hepatic fat mitochondrial oxidation, intrahepatic lipolysis, gluconeogenesis, and lipid accumulation.
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http://dx.doi.org/10.1016/j.cmet.2024.07.016 | DOI Listing |
Aquat Toxicol
December 2024
Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China; Sanya Institute of Ocean Eco-Environmental Engineering, Sanya 572025, China. Electronic address:
Arsenic (As) is widely recognized for its hazards to aquatic organisms; however, its toxicological impacts on apoptosis in marine fish remain inadequately explored. This study investigated the effects of in vivo dietary exposure to 50 or 500 mg/kg AsIII (as NaAsO) over 28 days in marine medaka, alongside in vitro exposure to 50-750 μg/L AsIII for 48 h in a hepatic cell line derived from marine medaka, to elucidate the toxicity and underlying molecular mechanisms. In vivo, As significantly accumulated in liver tissue (1.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
January 2025
Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892.
Mitochondrial endonuclease G (EndoG) contributes to chromosomal degradation when it is released from mitochondria during apoptosis. It is presumed to also have a mitochondrial function because EndoG deficiency causes mitochondrial dysfunction. However, the mechanism by which EndoG regulates mitochondrial function is not known.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
University of Kansas Alzheimer's Disease Research Center, Fairway, KS, USA.
Background: Altered liver function and dysregulated metabolism are emerging risk factors for Alzheimer's disease (AD). This includes genetic variation in apolipoprotein E (APOE), which is the strongest genetic risk determinant for AD. APOE is highly secreted by hepatocytes in the liver and astrocytes in the brain and plays a significant role in lipid homeostasis and metabolic function.
View Article and Find Full Text PDFMol Metab
December 2024
Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, Stippeneng 4, 6708 WE Wageningen, the Netherlands; Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA. Electronic address:
The peroxisome proliferator-activated receptor-alpha (PPARα) plays a central role in lipid metabolism in the liver by stimulating the expression of hundreds of genes. Accordingly, regulation by PPARα could be a screening tool to identify novel genes involved in hepatic lipid metabolism. Previously, the mitochondrial transporter SLC25A47 was suggested to play a role in energy metabolism and liver-specific uncoupling, but further research is lacking.
View Article and Find Full Text PDFFree Radic Biol Med
December 2024
Institute of Biomedicine of Seville (IBiS), Hospital University "Virgen del Rocío"/CSIC/University of Seville, Seville, Spain; Department of Medical Physiology and Biophysics, University of Seville, Seville, Spain; Biomedical Research Center for Hepatic and Digestive Diseases (CIBERehd), Madrid, Spain. Electronic address:
Background: Sorafenib is a tyrosine kinase inhibitor (TKI) that belongs to the landscape of treatments for advanced stages of hepatocellular carcinoma (HCC). The induction of cell death and cell cycle arrest by Sorafenib has been associated with mitochondrial dysfunction in liver cancer cells. Our research aim was to decipher underlying oxidative and nitrosative stress induced by Sorafenib leading to mitochondrial dysfunction in liver cancer cells.
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