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Von Willebrand A Domain-Containing Protein 8 (VWA8) is a poorly-characterized, mitochondrial matrix-targeted protein with a AAA ATPase domain and ATPase activity that rises in abundance in livers of high fat fed mice. This study was undertaken to use CRISPR/Cas9 to delete VWA8 in cultured mouse hepatocytes and gain insight into its function. Unbiased omics techniques and bioinformatics were used to guide subsequent assays, including assessment of oxidative stress and determination of bioenergetic capacity. Metabolomics analysis showed VWA8 null cells had higher oxidative stress and protein degradation; assays of hydrogen peroxide production revealed higher production of reactive oxygen species (ROS). Proteomics and transcriptomics analyses showed VWA8 null cells had higher expression of mitochondrial proteins (electron transport chain Complex I, ATP synthase), peroxisomal proteins, and lipid transport proteins. The pattern of higher protein abundance in the VWA8 null cells could be explained by higher hepatocyte nuclear factor 4 alpha (HNF4a) expression. Bioenergetic assays showed higher rates of carbohydrate oxidation and mitochondrial and non-mitochondrial lipid oxidation in intact and permeabilized cells. Inhibitor assays localized sites of ROS production to peroxisomes and NOX1/4. Rescue of VWA8 protein restored the wildtype phenotype and treatment with antioxidants lowered HNF4a expression. Thus, loss of VWA8 produces a mitochondrial defect that may be sensed by NOX4, leading to a rise in ROS that results in higher HNF4a. The compensatory HNF4a response results in higher oxidative capacity and even higher ROS production. We hypothesize that VWA8 is a AAA ATPase protein that plays a role in mitochondrial protein quality.
This article was published in the following journal.
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