Cited by 702MicroRNA in disease regulationMitochondrial Function and PathologyMetalloenzymes and iron-sulfur proteins

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MicroRNA-210 Controls Mitochondrial Metabolism during Hypoxia by Repressing the Iron-Sulfur Cluster Assembly Proteins ISCU1/2

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Chan, Stephen Y., Zhang, Ying-Yi, Hemann, Craig, Mahoney, Christopher E., Zweier, Jay L., Loscalzo, Joseph·2009·Cell Metabolism

DOI 10.1016/j.cmet.2009.08.015PMC PMC2759401

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Abstract

Repression of mitochondrial respiration represents an evolutionarily ancient cellular adaptation to hypoxia and profoundly influences cell survival and function; however, the underlying molecular mechanisms are incompletely understood. Primarily utilizing pulmonary arterial endothelial cells as a representative hypoxic cell type, we identify the iron-sulfur cluster assembly proteins (ISCU1/2) as direct targets for repression by the hypoxia-induced microRNA-210 (miR-210). ISCU1/2 facilitate the assembly of iron-sulfur clusters, prosthetic groups that are critical for electron transport and mitochondrial oxidation-reduction reactions. Under in vivo conditions of upregulating miR-210 and repressing ISCU1/2, the integrity of iron-sulfur clusters is disrupted. In turn, by repressing ISCU1/2 during hypoxia, miR-210 decreases the activity of prototypical iron-sulfur proteins controlling mitochondrial metabolism, including Complex I and aconitase. Consequently, miR-210 represses mitochondrial respiration and associated downstream functions. These results identify important mechanistic connections among microRNA, iron-sulfur cluster biology, hypoxia, and mitochondrial function, with broad implications for cellular metabolism and adaptation to cellular stress.

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Background
Retracted
HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia
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“In particular, this response may be especially important to the pulmonary vascular endothelium, which directly responds to hypoxia by controlling the release of vasoactive effectors, thereby critically influencing normal vascular physiology and the development of pulmonary hypertension (Stenmark et al., 2006).”
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“Some, but not all, of these miRNA have been identified in other transformed (Kulshreshtha et al., 2007) or primary endothelial cells (Fasanaro et al., 2008) exposed to hypoxia.”
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“Additionally, miR-210 is specifically induced by HIF-1a but not HIF-2a (Camps et al., 2008), a second transcriptional regulator of the hypoxic response, which carries partial but not full redundancy in function with HIF-1a (Wang et al., 2005).”
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Seagroves, T. N., Ryan, H. E., Lu, H., Wouters, B. G., Knapp, M., Thibault, P., Laderoute, K. R., & Johnson, R. S. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.10.3436-3444.2001 · Cited by 634 · cited 4×
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Additional file 13 of Iron-sulphur cluster biogenesis factor LYRM4 is a novel prognostic biomarker associated with immune infiltrates in hepatocellular carcinoma
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Additional file 8 of Iron-sulphur cluster biogenesis factor LYRM4 is a novel prognostic biomarker associated with immune infiltrates in hepatocellular carcinoma
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Additional file 6 of Iron-sulphur cluster biogenesis factor LYRM4 is a novel prognostic biomarker associated with immune infiltrates in hepatocellular carcinoma
Pang, Y., Tan, G., Yang, X., Lin, Y., Chen, Y., Zhang, J., Xie, T., Zhou, H., Fang, J., Zhao, Q., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16575551
Additional file 16 of Iron-sulphur cluster biogenesis factor LYRM4 is a novel prognostic biomarker associated with immune infiltrates in hepatocellular carcinoma
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Additional file 2 of SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress
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Additional file 11 of Iron-sulphur cluster biogenesis factor LYRM4 is a novel prognostic biomarker associated with immune infiltrates in hepatocellular carcinoma
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Additional file 9 of Iron-sulphur cluster biogenesis factor LYRM4 is a novel prognostic biomarker associated with immune infiltrates in hepatocellular carcinoma
Pang, Y., Tan, G., Yang, X., Lin, Y., Chen, Y., Zhang, J., Xie, T., Zhou, H., Fang, J., Zhao, Q., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16575497
Additional file 7 of Iron-sulphur cluster biogenesis factor LYRM4 is a novel prognostic biomarker associated with immune infiltrates in hepatocellular carcinoma
Pang, Y., Tan, G., Yang, X., Lin, Y., Chen, Y., Zhang, J., Xie, T., Zhou, H., Fang, J., Zhao, Q., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16575554
Additional file 1 of Iron-sulphur cluster biogenesis factor LYRM4 is a novel prognostic biomarker associated with immune infiltrates in hepatocellular carcinoma
Pang, Y., Tan, G., Yang, X., Lin, Y., Chen, Y., Zhang, J., Xie, T., Zhou, H., Fang, J., Zhao, Q., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16575524
Additional file 17 of Iron-sulphur cluster biogenesis factor LYRM4 is a novel prognostic biomarker associated with immune infiltrates in hepatocellular carcinoma
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Additional file 10 of Iron-sulphur cluster biogenesis factor LYRM4 is a novel prognostic biomarker associated with immune infiltrates in hepatocellular carcinoma
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Additional file 15 of Iron-sulphur cluster biogenesis factor LYRM4 is a novel prognostic biomarker associated with immune infiltrates in hepatocellular carcinoma
Pang, Y., Tan, G., Yang, X., Lin, Y., Chen, Y., Zhang, J., Xie, T., Zhou, H., Fang, J., Zhao, Q., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16575515
Additional file 5 of Iron-sulphur cluster biogenesis factor LYRM4 is a novel prognostic biomarker associated with immune infiltrates in hepatocellular carcinoma
Pang, Y., Tan, G., Yang, X., Lin, Y., Chen, Y., Zhang, J., Xie, T., Zhou, H., Fang, J., Zhao, Q., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16575548
Additional file 1 of SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress
Li, Q., Liu, M., Sun, Y., Jin, T., Zhu, P., Wan, X., Hou, Y., & Tu, G. (2021) · Figshare · doi:10.6084/m9.figshare.14600485
Additional file 12 of Iron-sulphur cluster biogenesis factor LYRM4 is a novel prognostic biomarker associated with immune infiltrates in hepatocellular carcinoma
Pang, Y., Tan, G., Yang, X., Lin, Y., Chen, Y., Zhang, J., Xie, T., Zhou, H., Fang, J., Zhao, Q., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16575506
Additional file 14 of Iron-sulphur cluster biogenesis factor LYRM4 is a novel prognostic biomarker associated with immune infiltrates in hepatocellular carcinoma
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Additional file 4 of Iron-sulphur cluster biogenesis factor LYRM4 is a novel prognostic biomarker associated with immune infiltrates in hepatocellular carcinoma
Pang, Y., Tan, G., Yang, X., Lin, Y., Chen, Y., Zhang, J., Xie, T., Zhou, H., Fang, J., Zhao, Q., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16575545
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miRNA-210 expression is associated with iron deficiency and biochemical parameters in hemodialysis patients
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Self-citation
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Authors: Chan, S. Y., Zhang, Y.-Y., Hemann, C., Mahoney, C. E., Zweier, J. L., & Loscalzo, J.
Affiliations: Harvard University (US)
The Ohio State University (US)
Brigham and Women's Hospital (US)
Corresponding author: Loscalzo, Joseph
ORCID: Chan, Stephen Y.
Hemann, Craig
Mahoney, Christopher E.
Zweier, Jay L.
Loscalzo, Joseph
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2009-10
Volume: 10
Issue: 4
Pages: 273-284
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2009.08.015
PMC: PMC2759401
OpenAlex: W2087408461
Cited by: 702
References: 37
Citations by year: 2026: 33 · 2025: 44 · 2024: 30 · 2023: 24 · 2022: 45 · 2021: 73 · 2020: 44 · 2019: 50 · 2018: 29 · 2017: 51 · 2016: 35 · 2015: 38 · 2014: 59 · 2013: 60 · 2012: 39
FWCI: 9.61
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1385 d)
Locations: Cell Metabolism (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (n01hv28178-12-0-0)
U.S. Public Health Service (P01 81587)
National Heart, Lung, and Blood Institute (HL61795, K08HL096834, U54HL070819, P01HL081587, N01-HV-028178, R21HL089734, R01HL061795, R37HL061795)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Metalloenzymes and iron-sulfur proteins
Keywords: miR-210, iron-sulfur cluster assembly, hypoxia, mitochondrial metabolism, mitochondrial respiration, pulmonary artery endothelial cells, complex I, aconitase, iron-sulfur proteins
MeSH terms: Animals, Hypoxia, Cells, Cultured, Gene Expression Regulation, Humans, Iron-Sulfur Proteins, Mitochondria, Oxygen Consumption, Mice, Knockout, MicroRNAs, Endothelial Cells, Mice, Von Hippel-Lindau Tumor Suppressor Protein, Caspase 3, Caspase 7

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MicroRNA-210 Controls Mitochondrial Metabolism during Hypoxia by Repressing the Iron-Sulfur Cluster Assembly Proteins ISCU1/2

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