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Impaired oxygen-sen...
Impaired oxygen-sensitive regulation of mitochondrial biogenesis within the von Hippel–Lindau syndrome
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- Li, Shuijie (author)
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; College of Pharmacy, Harbin Medical University, Harbin, China
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- Li, Wenyu (author)
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
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- Yuan, Juan (author)
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
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- Bullova, Petra (author)
- Karolinska Institutet
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- Wu, Jieyu (author)
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
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- Zhang, Xuepei (author)
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
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- Liu, Yong (author)
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
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- Plescher, Monika (author)
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
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- Rodriguez, Javier (author)
- Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh, United Kingdom
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- Bedoya-Reina, Oscar C. (author)
- Karolinska Institutet
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- Jannig, Paulo R. (author)
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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- Valente-Silva, Paula (author)
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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- Yu, Meng (author)
- Department of Medicine, Karolinska University Hospital, Stockholm, Sweden
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- Henriksson, Marie Arsenian (author)
- Karolinska Institutet
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- Zubarev, Roman A. (author)
- Karolinska Institutet
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- Smed-Sörensen, Anna (author)
- Karolinska Institutet
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- Suzuki, Carolyn K. (author)
- Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University-New Jersey Medical School, NJ, Newark, United States
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- Ruas, Jorge L. (author)
- Karolinska Institutet
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- Holmberg, Johan (author)
- Karolinska Institutet,Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten)
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- Larsson, Catharina (author)
- Karolinska Institutet
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- Christofer Juhlin, C. (author)
- Karolinska Institutet
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- von Kriegsheim, Alex (author)
- Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh, United Kingdom
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- Cao, Yihai (author)
- Karolinska Institutet
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- Schlisio, Susanne (author)
- Karolinska Institutet
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(creator_code:org_t)
- 2022-06-27
- 2022
- English.
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In: Nature Metabolism. - : Nature Publishing Group. - 2522-5812. ; 4:6, s. 739-758
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- Mitochondria are the main consumers of oxygen within the cell. How mitochondria sense oxygen levels remains unknown. Here we show an oxygen-sensitive regulation of TFAM, an activator of mitochondrial transcription and replication, whose alteration is linked to tumours arising in the von Hippel–Lindau syndrome. TFAM is hydroxylated by EGLN3 and subsequently bound by the von Hippel–Lindau tumour-suppressor protein, which stabilizes TFAM by preventing mitochondrial proteolysis. Cells lacking wild-type VHL or in which EGLN3 is inactivated have reduced mitochondrial mass. Tumorigenic VHL variants leading to different clinical manifestations fail to bind hydroxylated TFAM. In contrast, cells harbouring the Chuvash polycythaemia VHLR200W mutation, involved in hypoxia-sensing disorders without tumour development, are capable of binding hydroxylated TFAM. Accordingly, VHL-related tumours, such as pheochromocytoma and renal cell carcinoma cells, display low mitochondrial content, suggesting that impaired mitochondrial biogenesis is linked to VHL tumorigenesis. Finally, inhibiting proteolysis by targeting LONP1 increases mitochondrial content in VHL-deficient cells and sensitizes therapy-resistant tumours to sorafenib treatment. Our results offer pharmacological avenues to sensitize therapy-resistant VHL tumours by focusing on the mitochondria.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Li, Shuijie
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Li, Wenyu
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Yuan, Juan
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Bullova, Petra
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Wu, Jieyu
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Zhang, Xuepei
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show more...
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Liu, Yong
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Plescher, Monika
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Rodriguez, Javie ...
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Bedoya-Reina, Os ...
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Jannig, Paulo R.
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Valente-Silva, P ...
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Yu, Meng
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Henriksson, Mari ...
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Zubarev, Roman A ...
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Smed-Sörensen, A ...
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Suzuki, Carolyn ...
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Ruas, Jorge L.
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Holmberg, Johan
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Larsson, Cathari ...
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Christofer Juhli ...
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von Kriegsheim, ...
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Cao, Yihai
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Schlisio, Susann ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Nature Metabolis ...
- By the university
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Umeå University
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Karolinska Institutet