Apr 23, 2020

Endoplasmic Reticulum Associated Degradation (ERAD) Deficiency Promotes Mitochondrial Dysfunction and Transcriptional Rewiring in Human Hepatic Cells

BioRxiv : the Preprint Server for Biology
X. YangQiaomin Long

Abstract

Mitochondrial dysfunction has been associated with a variety of human diseases including neurodegeneration, diabetes, non-alcohol fatty liver disease (NAFLD) and cancer, but its underlying causes are incompletely understood. Endoplasmic reticular associated degradation (ERAD) is a protein quality control process essential for maintaining ER homeostasis. Using the human hepatic cell line HepG2 as a model, we show here that ERAD is critically required for mitochondrial function in mammalian cells. Pharmacological inhibition or genetic ablation of ERAD increases cell death under both basal conditions and in response to proinflammatory cytokines. 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 (MOMP). Transcriptome profiling reveals widespread down-regulation in the expression of genes underpinning mitochondrial functions, and up-regulation in the genes with association to tumor growth and aggression. These results highlight a critical role for ERAD in maintaining mitochondrial functional and structural integrity and raise the possibility to im...Continue Reading

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Mentioned in this Paper

Study
Immune System
Virus
Fatty Streaks
Genome
Brown Tendon Sheath Syndrome
Persons
Etiology
Manihot
Chemical Substitution

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