Mitochondrial Ndufa4l2 Enhances Deposition of Lipids and Expression of Ca9 in the TRACK Model of Early Clear Cell Renal Cell Carcinoma
Mitochondrial dysfunction and aberrant glycolysis are hallmarks of human clear cell renal cell carcinoma (ccRCC). Whereas glycolysis is thoroughly studied, little is known about the mitochondrial contribution to the pathology of ccRCC. Mitochondrial Ndufa4l2 is predictive of poor survival of ccRCC p...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-12-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.783856/full |
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| author | Kristian B. Laursen Qiuying Chen Francesca Khani Francesca Khani Nabeel Attarwala Steve S. Gross Lukas Dow Lukas Dow Lukas Dow David M. Nanus David M. Nanus Lorraine J. Gudas Lorraine J. Gudas |
| author_facet | Kristian B. Laursen Qiuying Chen Francesca Khani Francesca Khani Nabeel Attarwala Steve S. Gross Lukas Dow Lukas Dow Lukas Dow David M. Nanus David M. Nanus Lorraine J. Gudas Lorraine J. Gudas |
| author_sort | Kristian B. Laursen |
| collection | DOAJ |
| description | Mitochondrial dysfunction and aberrant glycolysis are hallmarks of human clear cell renal cell carcinoma (ccRCC). Whereas glycolysis is thoroughly studied, little is known about the mitochondrial contribution to the pathology of ccRCC. Mitochondrial Ndufa4l2 is predictive of poor survival of ccRCC patients, and in kidney cancer cell lines the protein supports proliferation and colony formation. Its role in ccRCC, however, remains enigmatic. We utilized our established ccRCC model, termed Transgenic Cancer of the Kidney (TRACK), to generate a novel genetically engineered mouse model in which dox-regulated expression of an shRNA decreases Ndufa4l2 levels specifically in the renal proximal tubules (PT). This targeted knockdown of Ndufa4l2 reduced the accumulation of neutral renal lipid and was associated with decreased levels of the ccRCC markers carbonic anhydrase 9 (CA9) and Enolase 1 (ENO1). These findings suggest a link between mitochondrial dysregulation (i.e. high levels of Ndufa4l2), lipid accumulation, and the expression of ccRCC markers ENO1 and CA9, and demonstrate that lipid accumulation and ccRCC development can potentially be attenuated by inhibiting Ndufa4l2. |
| first_indexed | 2024-12-22T21:16:48Z |
| format | Article |
| id | doaj.art-dd4a4b42337140b1bc8648e4e0f89432 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-22T21:16:48Z |
| publishDate | 2021-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-dd4a4b42337140b1bc8648e4e0f894322022-12-21T18:12:21ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-12-011110.3389/fonc.2021.783856783856Mitochondrial Ndufa4l2 Enhances Deposition of Lipids and Expression of Ca9 in the TRACK Model of Early Clear Cell Renal Cell CarcinomaKristian B. Laursen0Qiuying Chen1Francesca Khani2Francesca Khani3Nabeel Attarwala4Steve S. Gross5Lukas Dow6Lukas Dow7Lukas Dow8David M. Nanus9David M. Nanus10Lorraine J. Gudas11Lorraine J. Gudas12Department of Pharmacology, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, United StatesDepartment of Pharmacology, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, United StatesDepartment of Pathology and Laboratory Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, United StatesDepartment of Urology, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, United StatesDepartment of Pharmacology, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, United StatesDepartment of Pharmacology, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, United StatesDepartment of Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, United StatesDepartment of Biochemistry, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, United StatesGraduate School of Medical Sciences, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, United StatesDepartment of Urology, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, United StatesDivision of Hematology and Medical Oncology, Department of Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, United StatesDepartment of Pharmacology, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, United StatesDepartment of Urology, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, United StatesMitochondrial dysfunction and aberrant glycolysis are hallmarks of human clear cell renal cell carcinoma (ccRCC). Whereas glycolysis is thoroughly studied, little is known about the mitochondrial contribution to the pathology of ccRCC. Mitochondrial Ndufa4l2 is predictive of poor survival of ccRCC patients, and in kidney cancer cell lines the protein supports proliferation and colony formation. Its role in ccRCC, however, remains enigmatic. We utilized our established ccRCC model, termed Transgenic Cancer of the Kidney (TRACK), to generate a novel genetically engineered mouse model in which dox-regulated expression of an shRNA decreases Ndufa4l2 levels specifically in the renal proximal tubules (PT). This targeted knockdown of Ndufa4l2 reduced the accumulation of neutral renal lipid and was associated with decreased levels of the ccRCC markers carbonic anhydrase 9 (CA9) and Enolase 1 (ENO1). These findings suggest a link between mitochondrial dysregulation (i.e. high levels of Ndufa4l2), lipid accumulation, and the expression of ccRCC markers ENO1 and CA9, and demonstrate that lipid accumulation and ccRCC development can potentially be attenuated by inhibiting Ndufa4l2.https://www.frontiersin.org/articles/10.3389/fonc.2021.783856/fullclear cell renal cell carcinomahypoxiaHIF1von Hippel-Lindauproximal tubuleslipids |
| spellingShingle | Kristian B. Laursen Qiuying Chen Francesca Khani Francesca Khani Nabeel Attarwala Steve S. Gross Lukas Dow Lukas Dow Lukas Dow David M. Nanus David M. Nanus Lorraine J. Gudas Lorraine J. Gudas Mitochondrial Ndufa4l2 Enhances Deposition of Lipids and Expression of Ca9 in the TRACK Model of Early Clear Cell Renal Cell Carcinoma Frontiers in Oncology clear cell renal cell carcinoma hypoxia HIF1 von Hippel-Lindau proximal tubules lipids |
| title | Mitochondrial Ndufa4l2 Enhances Deposition of Lipids and Expression of Ca9 in the TRACK Model of Early Clear Cell Renal Cell Carcinoma |
| title_full | Mitochondrial Ndufa4l2 Enhances Deposition of Lipids and Expression of Ca9 in the TRACK Model of Early Clear Cell Renal Cell Carcinoma |
| title_fullStr | Mitochondrial Ndufa4l2 Enhances Deposition of Lipids and Expression of Ca9 in the TRACK Model of Early Clear Cell Renal Cell Carcinoma |
| title_full_unstemmed | Mitochondrial Ndufa4l2 Enhances Deposition of Lipids and Expression of Ca9 in the TRACK Model of Early Clear Cell Renal Cell Carcinoma |
| title_short | Mitochondrial Ndufa4l2 Enhances Deposition of Lipids and Expression of Ca9 in the TRACK Model of Early Clear Cell Renal Cell Carcinoma |
| title_sort | mitochondrial ndufa4l2 enhances deposition of lipids and expression of ca9 in the track model of early clear cell renal cell carcinoma |
| topic | clear cell renal cell carcinoma hypoxia HIF1 von Hippel-Lindau proximal tubules lipids |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.783856/full |
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