CHCHD4 Regulates Intracellular Oxygenation and Perinuclear Distribution of Mitochondria
Hypoxia is a characteristic of the tumor microenvironment and is known to contribute to tumor progression and treatment resistance. Hypoxia-inducible factor (HIF) dimeric transcription factors control the cellular response to reduced oxygenation by regulating the expression of genes involved in meta...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-04-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2017.00071/full |
| _version_ | 1811236252177924096 |
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| author | Luke W. Thomas Oliver Staples Mark Turmaine Margaret Ashcroft |
| author_facet | Luke W. Thomas Oliver Staples Mark Turmaine Margaret Ashcroft |
| author_sort | Luke W. Thomas |
| collection | DOAJ |
| description | Hypoxia is a characteristic of the tumor microenvironment and is known to contribute to tumor progression and treatment resistance. Hypoxia-inducible factor (HIF) dimeric transcription factors control the cellular response to reduced oxygenation by regulating the expression of genes involved in metabolic adaptation, cell motility, and survival. Alterations in mitochondrial metabolism are not only a downstream consequence of HIF-signaling but mitochondria reciprocally regulate HIF signaling through multiple means, including oxygen consumption, metabolic intermediates, and reactive oxygen species generation. CHCHD4 is a redox-sensitive mitochondrial protein, which we previously identified and showed to be a novel regulator of HIF and hypoxia responses in tumors. Elevated expression of CHCHD4 in human tumors correlates with the hypoxia gene signature, disease progression, and poor patient survival. Here, we show that either long-term (72 h) exposure to hypoxia (1% O2) or elevated expression of CHCHD4 in tumor cells in normoxia leads to perinuclear accumulation of mitochondria, which is dependent on the expression of HIF-1α. Furthermore, we show that CHCHD4 is required for perinuclear localization of mitochondria and HIF activation in response to long-term hypoxia. Mutation of the functionally important highly conserved cysteines within the Cys-Pro-Cys motif of CHCHD4 or inhibition of complex IV activity (by sodium azide) redistributes mitochondria from the perinuclear region toward the periphery of the cell and blocks HIF activation. Finally, we show that CHCHD4-mediated perinuclear localization of mitochondria is associated with increased intracellular hypoxia within the perinuclear region and constitutive basal HIF activation in normoxia. Our study demonstrates that the intracellular distribution of the mitochondrial network is an important feature of the cellular response to hypoxia, contributing to hypoxic signaling via HIF activation and regulated by way of the cross talk between CHCHD4 and HIF-1α. |
| first_indexed | 2024-04-12T12:05:52Z |
| format | Article |
| id | doaj.art-7b58d9a24a504b3e9db54775441d8a2e |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-12T12:05:52Z |
| publishDate | 2017-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-7b58d9a24a504b3e9db54775441d8a2e2022-12-22T03:33:42ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2017-04-01710.3389/fonc.2017.00071258750CHCHD4 Regulates Intracellular Oxygenation and Perinuclear Distribution of MitochondriaLuke W. Thomas0Oliver Staples1Mark Turmaine2Margaret Ashcroft3Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UKCentre for Cell Signalling and Molecular Genetics, Division of Medicine, University College London, London, UKDepartment of Cell and Developmental Biology, University College London, London, UKDepartment of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UKHypoxia is a characteristic of the tumor microenvironment and is known to contribute to tumor progression and treatment resistance. Hypoxia-inducible factor (HIF) dimeric transcription factors control the cellular response to reduced oxygenation by regulating the expression of genes involved in metabolic adaptation, cell motility, and survival. Alterations in mitochondrial metabolism are not only a downstream consequence of HIF-signaling but mitochondria reciprocally regulate HIF signaling through multiple means, including oxygen consumption, metabolic intermediates, and reactive oxygen species generation. CHCHD4 is a redox-sensitive mitochondrial protein, which we previously identified and showed to be a novel regulator of HIF and hypoxia responses in tumors. Elevated expression of CHCHD4 in human tumors correlates with the hypoxia gene signature, disease progression, and poor patient survival. Here, we show that either long-term (72 h) exposure to hypoxia (1% O2) or elevated expression of CHCHD4 in tumor cells in normoxia leads to perinuclear accumulation of mitochondria, which is dependent on the expression of HIF-1α. Furthermore, we show that CHCHD4 is required for perinuclear localization of mitochondria and HIF activation in response to long-term hypoxia. Mutation of the functionally important highly conserved cysteines within the Cys-Pro-Cys motif of CHCHD4 or inhibition of complex IV activity (by sodium azide) redistributes mitochondria from the perinuclear region toward the periphery of the cell and blocks HIF activation. Finally, we show that CHCHD4-mediated perinuclear localization of mitochondria is associated with increased intracellular hypoxia within the perinuclear region and constitutive basal HIF activation in normoxia. Our study demonstrates that the intracellular distribution of the mitochondrial network is an important feature of the cellular response to hypoxia, contributing to hypoxic signaling via HIF activation and regulated by way of the cross talk between CHCHD4 and HIF-1α.https://www.frontiersin.org/article/10.3389/fonc.2017.00071/fullhypoxiahypoxia-inducible factor-1αmitochondriamitochondrial localizationperinuclearcoiled-coil helix coiled-coil helix domain containing 4 |
| spellingShingle | Luke W. Thomas Oliver Staples Mark Turmaine Margaret Ashcroft CHCHD4 Regulates Intracellular Oxygenation and Perinuclear Distribution of Mitochondria Frontiers in Oncology hypoxia hypoxia-inducible factor-1α mitochondria mitochondrial localization perinuclear coiled-coil helix coiled-coil helix domain containing 4 |
| title | CHCHD4 Regulates Intracellular Oxygenation and Perinuclear Distribution of Mitochondria |
| title_full | CHCHD4 Regulates Intracellular Oxygenation and Perinuclear Distribution of Mitochondria |
| title_fullStr | CHCHD4 Regulates Intracellular Oxygenation and Perinuclear Distribution of Mitochondria |
| title_full_unstemmed | CHCHD4 Regulates Intracellular Oxygenation and Perinuclear Distribution of Mitochondria |
| title_short | CHCHD4 Regulates Intracellular Oxygenation and Perinuclear Distribution of Mitochondria |
| title_sort | chchd4 regulates intracellular oxygenation and perinuclear distribution of mitochondria |
| topic | hypoxia hypoxia-inducible factor-1α mitochondria mitochondrial localization perinuclear coiled-coil helix coiled-coil helix domain containing 4 |
| url | https://www.frontiersin.org/article/10.3389/fonc.2017.00071/full |
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