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Impact of Drp1 Loss on Organelle Interaction, Metabolism, and Inflammation in Mouse Liver

ABSTRACT: Dynamin-related protein 1 (Drp1) plays a critical role in mitochondrial fission and liver function. The interactions between mitochondria, endoplasmic reticulum (ER), and lipid droplets (LDs) are essential for lipid metabolism. In this study, liver-specific Drp1 knockout (Drp1LiKO) mice were utilized to investigate the impact of disrupted organelle interactions. Analysis revealed increased interactions between mitochondria and LDs, as well as among ER, mitochondria, and LDs in Drp1LiKO mice. As a result, impaired fatty acid metabolism was observed, leading to liver inflammation. In vitro studies using primary hepatocytes from Drp1LiKO mice further confirmed disrupted lipid metabolism and increased inflammation. These findings underscore the significance of Drp1 in maintaining organelle interactions for proper lipid metabolism and liver health. Targeting Drp1-mediated interactions may present a promising approach for the treatment of liver diseases associated with lipid metabolism dysregulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE296127 | GEO | 2025/05/01

REPOSITORIES: GEO

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Impact of Drp1 Loss on Organelle Interaction, Metabolism, and Inflammation in Mouse Liver

Project description:Dynamin-related protein 1 (Drp1) plays a critical role in mitochondrial fission and liver function. The interactions between mitochondria, endoplasmic reticulum (ER), and lipid droplets (LDs) are essential for lipid metabolism. In this study, liver-specific Drp1 knockout (Drp1LiKO) mice were utilized to investigate the impact of disrupted organelle interactions. Analysis revealed increased interactions between mitochondria and LDs, as well as among ER, mitochondria, and LDs in Drp1LiKO mice. As a result, impaired fatty acid metabolism was observed, leading to liver inflammation. In vitro studies using primary hepatocytes from Drp1LiKO mice further confirmed disrupted lipid metabolism and increased inflammation. These findings underscore the significance of Drp1 in maintaining organelle interactions for proper lipid metabolism and liver health. Tar-geting Drp1-mediated interactions may present a promising approach for the treatment of liver diseases associated with lipid metabolism dysregulation.

2025-05-01 | GSE296128 | GEO

Functional multi-organelle units control inflammatory lipid metabolism of macrophages

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Disruption of Drp1 in the liver protects mice against diet-induced obesity through induction of fibroblast growth factor 21

Project description:Mitochondria and the endoplasmic reticulum (ER) physically interact by close structural juxtaposition, via the mitochondrial-associated ER membrane. Recently, great advances have been made in the understanding of inter-organelle communication between the ER and mitochondria. To clarify the role of mitochondrial dynamics in this communication, we generated mice lacking the mitochondrial fission protein dynamin-related protein 1 (Drp1) in the liver (Drp1LiKO). While intake of a high-fat diet (HFD) resulted in histological changes characterized by hepatic steatosis, inflammation, apoptosis, necrosis and fibrosis, reminiscent of nonalcoholic steatohepatitis, Drp1LiKO mice showed decreased fat mass and were protected from HFD-induced obesity. Analysis of liver gene expression profiles demonstrated marked elevation of ER stress markers. In addition, we observed increased expression of fibroblast growth factor 21 (Fgf21) through induction of activating transcription factor 4 and X-box binding protein 1, master regulators of the integrated stress response.

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Organelle interactions compartmentalize hepatic fatty acid trafficking and metabolism

Project description:Organelle interactions play a significant role in compartmentalizing metabolism and signaling. Lipid droplets (LDs) interact with numerous organelles including mitochondria, which is largely assumed to facilitate lipid transfer and catabolism. However, quantitative proteomics of hepatic peridroplet (PDM) and cytosolic mitochondria (CM) revealed that CM are enriched in proteins comprising various oxidative metabolism pathways whereas PDM are enriched in proteins involved in lipid anabolism. Isotope tracing and super-resolution imaging confirmed that fatty acids (FAs) are selectively trafficked to and oxidized in CM during fasting. In contrast, PDM facilitate FA esterification and LD expansion in nutrient-replete media. Additionally, mitochondrial-associated membranes (MAMs) around PDM and CM differed in their proteomes and ability to support distinct lipid metabolic pathways. We conclude that CM and CM-MAM support lipid catabolic pathways whereas PDM and PDM-MAM allow hepatocytes to efficiently store excess lipids in LDs to prevent lipotoxicity in contrast to existing dogma.

2023-03-28 | MSV000091575 | MassIVE

Organelle interactions compartmentalize hepatic fatty acid trafficking and metabolism MAM Dataset

2023-03-28 | MSV000091576 | MassIVE

Alteration of Liver Peroxisomal and Mitochondrial Functionality in the NZO Mouse Model of Metabolic Syndrome.

Project description:Purpose: MetS consist of five risk factors: elevated blood pressure and fasting glucose, visceral obesity, dyslipidemia and hypercholesterinemia. The physiological impact of lipid metabolism indicated as visceral obesity and hepatic lipid accumulation is still under debate. One major cause of disturbed lipid metabolism might be dysfunction of cellular organelles controlling energy homeostasis, i.e. mitochondria and peroxisomes. Experimental design: The New Zealand Obese (NZO) mouse model exhibits a polygenic syndrome of obesity, insulin resistance, triglyceridemia and hypercholesterolemia that resembles human metabolic syndrome. We applied a combinatorial approach of lipidomics with liver transcriptomics, 2D-DIGETM and mass spectroscopy based organelle proteomics of highly purified mitochondria and peroxisomes in male mice, to investigate molecular mechanisms related to the impact of lipid metabolism in the pathophysiology of the metabolic syndrome. Conclusions and clinical relevance: Proteome analyses of liver organelles indicated differences in fatty acid metabolism, oxidative stress and response, mainly influenced by PG-C1α/PPARα mediated pathways. These results were in accordance with serum lipid profiles and elevated organelle functionality. These data emphasize that metabolic syndrome is accompanied with increased mitochondria and peroxisomal activity controlling directly cellular energy homeostasis to cope with dyslipidemia and hypercholesterinemia driven hepatic lipid overflow in developing a fatty liver.

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2018-01-15 | GSE70809 | GEO

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2024-02-26 | GSE256510 | GEO

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