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MicroRNA-210 Controls Mitochondrial Metabolism during Hypoxia by Repressing the Iron-Sulfur Cluster Assembly Proteins ISCU1/2
Open accessAbstract
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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“The coordinate metabolic changes caused by HIF-1 that alter mitochondrial function are attributable, in part, to the HIF-1-mediated transcriptional upregulation of microRNA 210 (miR210), which specifically inhibits Fe-S complex formation to alter mitochondrial bioenergetics and ROS production (Pasteur effect) (69).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [69]
In the citing paper
“Interestingly, during normoxia, forced expression of miR210 caused an increase in ROS generation (69, 81), possibly due to deficiencies in complex I that may promote electron leak in the presence of molecular oxygen.”
From Redox regulation of mitochondrial function (2012) · cites this paper as [69]
In the citing paper
“Nonetheless, experimental evidence suggests that enhanced ROS production is not a sustained event in hypoxia (69, 385).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [69]
In the citing paper
“Within mitochondria it targets regulatory proteins that assist in the assembly of the complexes of the electron transport chain, and suppresses respiration (103, 108).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [103]
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1 retracted
Mitochondrial Autophagy Is an HIF-1-dependent Adaptive Metabolic Response to Hypoxia
Zhang, H., Bosch-Marce, M., Shimoda, L. A., Tan, Y. S., Baek, J. H., Wesley, J. B., Gonzalez, F. J., & Semenza, G. L. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800102200 · Cited by 1,601 · cited 1×
“Mitophagy has been characterized as a HIF-dependent mechanism (Zhang et al., 2008).”
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Iron-sulfur clusters: nature's modular, multipurpose structures
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InfluentialHIF-1 Regulates Cytochrome Oxidase Subunits to Optimize Efficiency of Respiration in Hypoxic Cells
Fukuda, R., Zhang, H., Kim, J.-W., Shimoda, L., Dang, C. V., & Semenza, G. L. (2007) · Cell · doi:10.1016/j.cell.2007.01.047 · Cited by 1,225 · cited 1×
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Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1
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InfluentialHypoxia-Induced Pulmonary Vascular Remodeling
Stenmark, K. R., Fagan, K. A., & Frid, M. G. (2006) · Circulation Research · doi:10.1161/01.res.0000243584.45145.3f · Cited by 1,001 · cited 2×
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Fasanaro, P., D'Alessandra, Y., Di Stefano, V., Melchionna, R., Romani, S., Pompilio, G., Capogrossi, M. C., & Martelli, F. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m800731200 · Cited by 912 · cited 6×
“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.”
Influentialhsa-miR-210 Is Induced by Hypoxia and Is an Independent Prognostic Factor in Breast Cancer
Camps, C., Buffa, F. M., Colella, S., Moore, J., Sotiriou, C. P., Sheldon, H., Harris, A. L., Gleadle, J., & Ragoussis, J. (2008) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-07-1755 · Cited by 672 · cited 3×
“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).”
Transcription Factor HIF-1 Is a Necessary Mediator of the Pasteur Effect in Mammalian Cells
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×
“The elucidation of the miR-210-ISCU1/2 regulatory pathway substantially clarifies the nature of the complex crosstalk between HIF-1a and mitochondria (Seagroves et al., 2001) and complements other HIF-dependent processes proposed to regulate the mismatch of reduced oxygen tension and mitochondrial electron transport.”
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“…miR-210 is upregulated and targets iron-sulfur cluster assembly proteins ISCU1/2 that are critical for electron transport andmitochondrial oxidation/reduction, thereby shutting down the aerobic mitochondrial functions and switching the hypoxic cells to anaerobic metabolism (Chan et al., 2009).”
Lu, J., Tan, M., & Cai, Q. (2014) · Cancer Letters · doi:10.1016/j.canlet.2014.04.001 · Cited by 822
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“In addition to the direct regulation of genes encoding PDK1, BNIP3, COX4–2, and LON (a mitochondrial protease that is required for degradation of COX4–1), HIF-1 also activates transcription of the gene encoding microRNA miR-210, which inhibits expression of the iron-sulfur cluster assembly proteins ISCU1/2, which are…”
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“Nonetheless, experimental evidence suggests that enhanced ROS production is not a sustained event in hypoxia (69, 385).”
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“…report has shown that, besides regulating proteincoding genes expression, hypoxia/HIF-1a is able to induce expression of a microRNA-210, which in turn decreases the expression of the iron-sulfur cluster assembly proteins ISCU1/ 2, thereby repressing oxidative phosphorylation (Chan et al., 2009).”
BackgroundMitochondria and Endothelial Function
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“This response may be important for the Pasteur effect and the mammalian adaptation to hypoxia.(213) Given the recent interest in miRs as therapeutic targets,(212) these results suggest”
BackgroundCancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target
Infantino, V., Santarsiero, A., Convertini, P., Todisco, S., & Iacobazzi, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115703 · Cited by 541
“This small RNA inhibits expression of iron–sulfur cluster assembly proteins (ISCU1 and ISCU2) required for Complex I assembly [109].”
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“HIF-1 activates the transcription of the microRNA miR-210 in many cell types [10,31] andmiR-210was shown to block expression of the iron– sulfur cluster assembly proteins ISCU1/2, which are required for the function of the TCA cycle enzyme aconitase and ETC complex I [32].”
BackgroundMicroRNA-210 as a Novel Therapy for Treatment of Ischemic Heart Disease
Hu, S., Huang, M., Li, Z., Jia, F., Ghosh, Z., Lijkwan, M. A., Fasanaro, P., Sun, N., Wang, X., Martelli, F., et al. (2010) · Circulation · doi:10.1161/circulationaha.109.928424 · Cited by 462
microRNA Therapeutics in Cancer — An Emerging Concept
Shah, M., Ferrajoli, A., Sood, A. K., Lopez‐Berestein, G., & Călin, G. A. (2016) · EBioMedicine · doi:10.1016/j.ebiom.2016.09.017 · Cited by 461
“…2009); avoiding immune destruction (miR-520d) (Stern-Ginossar et al., 2008); deregulating cellular genetics (miR-122, miR-210) (Esau et al., 2006; Chan et al., 2009); tumor-promoting inflammation (miR146, miR-155) (Schetter et al., 2010); and genome instability and mutation (miR-155) (Valeri et…”
BackgroundVascular Endothelial Growth Factor Signaling in Hypoxia and Inflammation
Ramakrishnan, S., Anand, V., & Roy, S. (2014) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-014-9531-7 · Cited by 460
Baggish, A. L., Hale, A., Weiner, R. B., Lewis, G. D., Systrom, D., Wang, F., Wang, T. J., & Chan, S. Y. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2011.213363 · Cited by 431
“2010), mitochondrial metabolism (Chan et al. 2009; Dang, 2010), cardiac/skeletal muscle contractile force generation, and tissue hypertrophy (Williams et al.”
BackgroundSelf-citationHypoxia. 2. Hypoxia regulates cellular metabolism
Wheaton, W. W., & Chandel, N. S. (2011) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00485.2010 · Cited by 426
Du, J., Wang, T., Li, Y., Zhou, Y., Wang, X., Yu, X., Ren, X., An, Y., Wu, Y., Sun, W., et al. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.12.011 · Cited by 487
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“15 and the Iron Sulfur Cluster Assembly Proteins ISCU1s2”
BackgroundGhosh, G., Subramanian, I. V., Adhikari, N., Zhang, X., Joshi, H. P., Basi, D. L., Chandrashekhar, Y., Hall, J. L., Roy, S., Zeng, Y., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci42980 · Cited by 424
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“Similarly, HIF-1 appears to regulate the expression of certain cytochrome components directly and to regulate specific microRNAs that can in turn regulate the expression of components of the electron transport chain (17, 18).”
BackgroundHIF-1α protects against oxidative stress by directly targeting mitochondria
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“…metabolism, including inhibition of fatty acid oxidation, which also generates acetyl-CoA (Huang et al, 2014), induction of mitochondrial-selective autophagy (Zhang et al, 2008; Bellot et al, 2009), and inhibition of ETC complex I activity (Chan et al, 2009; Favaro et al, 2010; Tello et al, 2011).”
BackgroundChan, Y. C., Banerjee, J., Choi, S. Y., & Sen, C. K. (2011) · Microcirculation · doi:10.1111/j.1549-8719.2011.00154.x · Cited by 370
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BackgroundResultInfluentialSelf-citationReactive oxygen species, nutrition, hypoxia and diseases: Problems solved?
Görlach, A., Dimova, E. Y., Petry, A., Martínez-Ruiz, A., Hernansanz‐Agustín, P., Rolo, A. P., Palmeira, C. M., & Kietzmann, T. (2015) · Redox Biology · doi:10.1016/j.redox.2015.08.016 · Cited by 364
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“suppresses iron-sulfur cluster assembly enzyme 1/2 (ISCU1/2) in complex I and III to reduce mitochondrial activity and ROS production under hypoxia [48] (Table 1).”
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Self-citationOxygen Sensing and Homeostasis
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“For example, miR-210 regulates mitochondrial respiration and metabolism during hypoxic stress by repressing the IronSulfur Cluster Assembly Proteins ISCU1/2 [82].”
BackgroundFumarate is a terminal electron acceptor in the mammalian electron transport chain
Spinelli, J. B., Rosen, P. C., Sprenger, H.-G., Puszynska, A. M., Mann, J. L., Roessler, J. M., Cangelosi, A. L., Henne, A., Condon, K. J., Zhang, T., et al. (2021) · Science · doi:10.1126/science.abi7495 · Cited by 221
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“2696 fur cluster stability and aconitase activity due to downregulation of the protein ISCU1/2 (11, 12, 19).”
BackgroundAMPK–mTOR Signaling and Cellular Adaptations in Hypoxia
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MiR-210 promotes a hypoxic phenotype and increases radioresistance in human lung cancer cell lines
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“By reducing the metabolism of mitochondria in normoxia, miR-210 would create a mitochondrial dysfunction that is known to lead to an increase in toxic reactive oxygen species (ROS).(25) Adaptation of cells to an increased ROS production may be part of the mechanism that protects cells against radiation exposure.”
BackgroundCross Talk of Combined Gene and Cell Therapy in Ischemic Heart Disease
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“Iron-sulfur cluster scaffold homolog (Iscu) is a validated target of miR-210, which on repression, reduces mitochondrial metabolism.(17) A significant reduction of Iscu was observed in CPCs treated with EC-Exo indicative of repression through miR-210 (Figure 5D).”
BackgroundExploring the molecular interface between hypoxia-inducible factor signalling and mitochondria
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MitomiRs in human inflamm-aging: A hypothesis involving miR-181a, miR-34a and miR-146a
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“…(it represses expression of the mitochondrial iron sulfur cluster homolog ISCU, thus affecting aconitase and mitochondrial complex activity) (Chan et al., 2009) (Favaro et al., 2010); and let-7b, which seems to have several potential mitochondrial targets, i.e. ATP6 (ATP synthase F0 subunit…”
BackgroundHypoxia-inducible factors and their roles in energy metabolism
Goda, N., & Kanai, M. (2012) · International Journal of Hematology · doi:10.1007/s12185-012-1069-y · Cited by 221
“In response to hypoxia, HIF-1 has recently been reported to induce transcription of a microRNA, miR-210, which decreases expression of iron-sulfur scaffold proteins ISCU1/2, essential components for assembly of iron–sulfur cluster [22].”
BackgroundOxygen availability and metabolic reprogramming in cancer
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Roles of microRNA on cancer cell metabolism
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“…(physiological) response to continuous hypoxia, in which HIF-1 mediates the expression of multiple pathways that modulate or decrease mitochondrial respiration and ROS generation (Kim et al., 2006; Fukuda et al., 2007; Zhang et al., 2008a; Chan et al., 2009; Chen et al., 2010; Favaro et al., 2010).”
BackgroundOxidative Stress and MicroRNAs in Vascular Diseases
Magenta, A., Greco, S., Gaetano, C., & Martelli, F. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140917319 · Cited by 198
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“As an example, it was shown that human ISCU1/2 are repressed during hypoxia by the microRNA-210, as a way to control mitochondrial metabolism under this condition (Chan et al., 2009).”
BackgroundDisorders of cancer metabolism: The therapeutic potential of cannabinoids
Sun, D., Li, X., Nie, S., Liu, J., & Wang, S. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113993 · Cited by 195
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“miR-210 targets and downregulates ISCU1/2 via their 3' UTRs, resulting in disruption of TCA metabolism and compromised electron transport and energy production [40].”
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“In addition to the inhibitory effect on tumor growth, miR-210 can decrease mitochondrial function and up-regulate glycolysis of tumor cells under hypoxia, which helps cells adapt to hypoxic stress and survive.(5,6) Usually, hypoxia inside tumors can stimulate angiogenesis to sustain tumor growth.”
BackgroundMcCormick, R., Blick, C., Ragoussis, J., Schoedel, J., Mole, D. R., Young, A. C., Selby, P. J., Banks, R. E., & Harris, A. L. (2013) · British Journal of Cancer · doi:10.1038/bjc.2013.56 · Cited by 180
“It has been previously published by our group and others that ISCU is a miR-210 target (Chan et al, 2009; Chen et al, 2010; Favaro et al, 2010).”
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“miR-210 was also found to target the Iron-Sulfur Cluster Assembly Proteins ISCU1/2 to control mitochondrial metabolism during hypoxia [20].”
BackgroundMicroRNA-210 overexpression induces angiogenesis and neurogenesis in the normal adult mouse brain
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MicroRNA-210 Controls Mitochondrial Metabolism and Protects Heart Function in Myocardial Infarction
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“The role of miR-210 during hypoxia is suggested to involve repression of mitochondrial metabolism, which is considered an important factor for aerobic fitness [33].”
BackgroundMultiple functions of hypoxia-regulated miR-210 in cancer
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“regulation [18,22,26-30], cell survival [31-36], differentiation [37-40], angiogenesis [41-51] as well as metabolism [52-57].”
BackgroundHypoxia-regulated microRNAs in human cancer
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“We have defined a large number of potential miR-210 targets using such methodology, and during the course of this study Chan and colleagues [57] and subsequently others [58-60] were able to experimentally validate the regulation of one such predicted target, ISCU1/2.”
MitomiRs delineating the intracellular localization of microRNAs at mitochondria
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“microRNAs play a role in angiogenesis [214], inflammation [215], the regulation of muscle contraction [216], the response to hypoxia [217], and mitochondrial metabolism [218].”
BackgroundAcclimatization of skeletal muscle mitochondria to high‐altitude hypoxia during an ascent of Everest
Levett, D. Z. H., Radford, E. J., Menassa, D. A., Graber, E. F., Morash, A. J., Hoppeler, H. H., Clarke, K., Martín, D., Ferguson‐Smith, A. C., Montgomery, H., et al. (2011) · The FASEB Journal · doi:10.1096/fj.11-197772 · Cited by 157
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“metabolism.(17) Furthermore, another direct target of miR-210, known as ‘max-binding protein’, controls the cell cycle and proliferation through reciprocal upregulation of c-myc activity.”
BackgroundGiraud‐Billoud, M., Rivera‐Ingraham, G. A., Moreira, D. C., Burmester, T., Castro‐Vazquez, A., Carvajalino-Fernández, J. M., Dafré, A. L., Niu, C., Tremblay, N., Paital, B., et al. (2019) · Comparative Biochemistry and Physiology Part A Molecular & Integrative Physiology · doi:10.1016/j.cbpa.2019.04.004 · Cited by 151
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Responses to reductive stress in the cardiovascular system
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“In particular, the hypoxamir miR-210 concurrently suppresses the expression of the iron sulfur-cluster scaffold proteins ISCU1/2 to decrease the activity of iron sulfur cluster-containing enzymes, such as complex I of the mitochondrial electron transport chain and aconitase of the TCA cycle [77].”
BackgroundSelf-citation
Metadata
- 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
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2009-10
- Volume
- 10
- Issue
- 4
- Pages
- 273-284
- ISSN
- 1550-4131 (ISSN-L)
- 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
- 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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