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ERAD deficiency promotes mitochondrial dysfunction and transcriptional rewiring in human hepatic cells.

ABSTRACT: Mitochondrial dysfunction is associated with a variety of human diseases including neurodegeneration, diabetes, nonalcohol fatty liver disease (NAFLD), and cancer, but its underlying causes are incompletely understood. Using the human hepatic cell line HepG2 as a model, we show here that endoplasmic reticulum-associated degradation (ERAD), an ER protein quality control process, is critically required for mitochondrial function in mammalian cells. Pharmacological inhibition or genetic ablation of key proteins involved in ERAD increased cell death under both basal conditions and in response to proinflammatory cytokines, a situation frequently found in NAFLD. Decreased viability of ERAD-deficient HepG2 cells was traced to impaired mitochondrial functions including reduced ATP production, enhanced reactive oxygen species (ROS) accumulation, and increased mitochondrial outer membrane permeability. Transcriptome profiling revealed widespread down-regulation of genes underpinning mitochondrial functions, and up-regulation of genes associated with tumor growth and aggression. These results highlight a critical role for ERAD in maintaining mitochondrial functional and structural integrity and raise the possibility of improving cellular and organismal mitochondrial function via enhancing cellular ERAD capacity.

SUBMITTER: Liu Q

PROVIDER: S-EPMC7864069 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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ERAD deficiency promotes mitochondrial dysfunction and transcriptional rewiring in human hepatic cells.

Liu Qingqing Q Yang Xiaoqin X Long Guangyu G Hu Yabing Y Gu Zhenglong Z Boisclair Yves R YR Long Qiaoming Q

The Journal of biological chemistry 20200925 49

Mitochondrial dysfunction is associated with a variety of human diseases including neurodegeneration, diabetes, nonalcohol fatty liver disease (NAFLD), and cancer, but its underlying causes are incompletely understood. Using the human hepatic cell line HepG2 as a model, we show here that endoplasmic reticulum-associated degradation (ERAD), an ER protein quality control process, is critically required for mitochondrial function in mammalian cells. Pharmacological inhibition or genetic ablation of ...[more]

PMID: 32978261

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Dataset Information

ERAD deficiency promotes mitochondrial dysfunction and transcriptional rewiring in human hepatic cells.

Publications

ERAD deficiency promotes mitochondrial dysfunction and transcriptional rewiring in human hepatic cells.

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