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.
Highlights
The endoplasmic reticulum (ER) serves several critical cellular functions, including Ca21 storage, lipid synthesis, and the folding of protein molecules destined for the secretory pathway
We recently showed that ER-associated degradation (ERAD) disruption reduces ATP production in rat pancreatic b-cell line INS-1, indicating that ERAD deficiency impairs mitochondrial respiratory function [15]
These results indicate that an effective ERAD is required to maintain normal mitochondrial function and cell viability in mammalian cells
Summary
The endoplasmic reticulum (ER) serves several critical cellular functions, including Ca21 storage, lipid synthesis, and the folding of protein molecules destined for the secretory pathway. ERAD-deficient cells show impaired ATP production, increased mitochondrial outer membrane permeability (MOMP), and enhanced sensitivity to tumor necrosis factor a (TNFa)-induced cell death These consequences of ERAD deficiency were associated with an altered gene expression profile characterized by the selective down-regulation of mitochondria-related and up-regulation of tumor growth and aggression-related genes. These results indicate that ERAD is critically required for maintaining normal mitochondrial function and ERAD deficiency may potential mammalian cells to adopt a tumorigenic molecular signature by activating the mitochondrial retrograde signaling pathway
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