Deletion of Von Willebrand A Domain Containing Protein (VWA8) raises activity of mitochondrial electron transport chain complexes in hepatocytes
VWA8 (Von Willebrand A Domain Containing Protein 8) is a AAA+ ATPase that is localized to the mitochondrial matrix and is widely expressed in highly energetic tissues. Originally found to be higher in abundance in livers of mice fed a high fat diet, deletion of the VWA8 gene in differentiated mouse...
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| Format: | Article |
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Elsevier
2021-07-01
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| Series: | Biochemistry and Biophysics Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405580821000224 |
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| author | Moulun Luo Wuqiong Ma Rocio Zapata-Bustos Wayne T. Willis Lawrence J. Mandarino |
| author_facet | Moulun Luo Wuqiong Ma Rocio Zapata-Bustos Wayne T. Willis Lawrence J. Mandarino |
| author_sort | Moulun Luo |
| collection | DOAJ |
| description | VWA8 (Von Willebrand A Domain Containing Protein 8) is a AAA+ ATPase that is localized to the mitochondrial matrix and is widely expressed in highly energetic tissues. Originally found to be higher in abundance in livers of mice fed a high fat diet, deletion of the VWA8 gene in differentiated mouse AML12 hepatocytes unexpectedly produced a phenotype of higher mitochondrial and nonmitochondrial oxidative metabolism, higher ROS (reactive oxygen species) production mainly from NADPH oxidases, and increased HNF4a expression. The purposes of this study were first, to determine whether higher mitochondrial oxidative capacity in VWA8 null hepatocytes is the product of higher capacity in all aspects of the electron transport chain and oxidative phosphorylation, and second, the density of cristae in mitochondria and mitochondrial content was measured to determine if higher mitochondrial oxidative capacity is accompanied by greater cristae area and mitochondrial abundance. Electron transport chain complexes I, II, III, and IV activities all were higher in hepatocytes in which the VWA8 gene had been deleted using CRISPR/Cas9. A comparison of abundance of proteins in electron transport chain complexes I, III and ATP synthase previously determined using an unbiased proteomics approach in hepatocytes in which VWA8 had been deleted showed agreement with the activity assays. Mitochondrial cristae, the site where electron transport chain complexes are located, were quantified using electron microscopy and stereology. Cristae density, per mitochondrial area, was almost two-fold higher in the VWA8 null cells (P < 0.01), and mitochondrial area was two-fold higher in the VWA8 null cells (P < 0.05). The results of this study allow us to conclude that despite sustained, higher ROS production in VWA8 null cells, a global mitochondrial compensatory response was maintained, resulting in overall higher mitochondrial oxidative capacity. |
| first_indexed | 2024-12-20T23:48:32Z |
| format | Article |
| id | doaj.art-76e6159e26e54edfbbb560d83072c3e0 |
| institution | Directory Open Access Journal |
| issn | 2405-5808 |
| language | English |
| last_indexed | 2024-12-20T23:48:32Z |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biochemistry and Biophysics Reports |
| spelling | doaj.art-76e6159e26e54edfbbb560d83072c3e02022-12-21T19:22:54ZengElsevierBiochemistry and Biophysics Reports2405-58082021-07-0126100928Deletion of Von Willebrand A Domain Containing Protein (VWA8) raises activity of mitochondrial electron transport chain complexes in hepatocytesMoulun Luo0Wuqiong Ma1Rocio Zapata-Bustos2Wayne T. Willis3Lawrence J. Mandarino4Department of Medicine, Division of Endocrinology, USADepartment of Medicine, Division of Endocrinology, USADepartment of Medicine, Division of Endocrinology, USADepartment of Medicine, Division of Endocrinology, USA; Center for Disparities in Diabetes, Obesity, and Metabolism, The University of Arizona, Tucson, AZ, 85724, USADepartment of Medicine, Division of Endocrinology, USA; Center for Disparities in Diabetes, Obesity, and Metabolism, The University of Arizona, Tucson, AZ, 85724, USA; Corresponding author. Division of Endocrinology, Department of Medicine, Center for Disparities in Diabetes, Obesity, and Metabolism, University of Arizona, 1501 N. Campbell Ave, Tucson, AZ, 85724, USA.VWA8 (Von Willebrand A Domain Containing Protein 8) is a AAA+ ATPase that is localized to the mitochondrial matrix and is widely expressed in highly energetic tissues. Originally found to be higher in abundance in livers of mice fed a high fat diet, deletion of the VWA8 gene in differentiated mouse AML12 hepatocytes unexpectedly produced a phenotype of higher mitochondrial and nonmitochondrial oxidative metabolism, higher ROS (reactive oxygen species) production mainly from NADPH oxidases, and increased HNF4a expression. The purposes of this study were first, to determine whether higher mitochondrial oxidative capacity in VWA8 null hepatocytes is the product of higher capacity in all aspects of the electron transport chain and oxidative phosphorylation, and second, the density of cristae in mitochondria and mitochondrial content was measured to determine if higher mitochondrial oxidative capacity is accompanied by greater cristae area and mitochondrial abundance. Electron transport chain complexes I, II, III, and IV activities all were higher in hepatocytes in which the VWA8 gene had been deleted using CRISPR/Cas9. A comparison of abundance of proteins in electron transport chain complexes I, III and ATP synthase previously determined using an unbiased proteomics approach in hepatocytes in which VWA8 had been deleted showed agreement with the activity assays. Mitochondrial cristae, the site where electron transport chain complexes are located, were quantified using electron microscopy and stereology. Cristae density, per mitochondrial area, was almost two-fold higher in the VWA8 null cells (P < 0.01), and mitochondrial area was two-fold higher in the VWA8 null cells (P < 0.05). The results of this study allow us to conclude that despite sustained, higher ROS production in VWA8 null cells, a global mitochondrial compensatory response was maintained, resulting in overall higher mitochondrial oxidative capacity.http://www.sciencedirect.com/science/article/pii/S2405580821000224VWA8HepatocytesElectron transport chainMitochondria |
| spellingShingle | Moulun Luo Wuqiong Ma Rocio Zapata-Bustos Wayne T. Willis Lawrence J. Mandarino Deletion of Von Willebrand A Domain Containing Protein (VWA8) raises activity of mitochondrial electron transport chain complexes in hepatocytes Biochemistry and Biophysics Reports VWA8 Hepatocytes Electron transport chain Mitochondria |
| title | Deletion of Von Willebrand A Domain Containing Protein (VWA8) raises activity of mitochondrial electron transport chain complexes in hepatocytes |
| title_full | Deletion of Von Willebrand A Domain Containing Protein (VWA8) raises activity of mitochondrial electron transport chain complexes in hepatocytes |
| title_fullStr | Deletion of Von Willebrand A Domain Containing Protein (VWA8) raises activity of mitochondrial electron transport chain complexes in hepatocytes |
| title_full_unstemmed | Deletion of Von Willebrand A Domain Containing Protein (VWA8) raises activity of mitochondrial electron transport chain complexes in hepatocytes |
| title_short | Deletion of Von Willebrand A Domain Containing Protein (VWA8) raises activity of mitochondrial electron transport chain complexes in hepatocytes |
| title_sort | deletion of von willebrand a domain containing protein vwa8 raises activity of mitochondrial electron transport chain complexes in hepatocytes |
| topic | VWA8 Hepatocytes Electron transport chain Mitochondria |
| url | http://www.sciencedirect.com/science/article/pii/S2405580821000224 |
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