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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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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).”
BackgroundRetractedKim, J.-W., Tchernyshyov, I., Semenza, G. L., & Dang, C. V. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.02.002 · Cited by 3,905 · cited 1×
“First, by induction of PDK1, HIF-1a decreases the activity of the TCA cycle, increases glycolysis, and reduces mitochondrial electron flux (Kim et al., 2006).”
Iron-sulfur clusters: nature's modular, multipurpose structures
Beinert, H., Holm, R. H., & Münck, E. (1997) · Science · doi:10.1126/science.277.5326.653 · Cited by 1,944 · cited 4×
“280 Cell Metabolism 10, 273–284, October 7, 2009 ª2009 Elsevier Inc. to oxidative stress (Beinert et al., 1997), along with repression of iron-sulfur cluster biogenesis via downregulated ISCU1/2, may provide a real-time redox-sensitive ‘‘switch’’ that is triggered by hypoxia to induce downstream…”
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×
“Second, HIF-1a induces a COX4-1 to COX4-2 subunit switch during hypoxia to improve the efficiency of electron transfer to oxygen at Complex IV (Fukuda et al., 2007).”
Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1
Manalo, D. J., Rowan, A., Lavoie, T., Natarajan, L., Kelly, B. D., Ye, S. Q., Garcia, J. G. N., & Semenza, G. L. (2005) · Blood · doi:10.1182/blood-2004-07-2958 · Cited by 1,154 · cited 1×
“Conditions were based on studies of hypoxic exposure of HPAECs (Manalo et al., 2005) to allow for steady-state adaptation without nonspecific cell death.”
A MicroRNA Signature of Hypoxia
Kulshreshtha, R., Ferracin, M., Wojcik, S. E., Garzon, R., Alder, H., Agosto-Perez, F. J., Davuluri, R., Liu, C.-G., Croce, C. M., Negrini, M., et al. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01395-06 · Cited by 1,055 · cited 5×
“…with other studies demonstrating the repression of apoptosis by miR-210 during hypoxia in other cellular contexts (Fasanaro et al., 2008; Kulshreshtha et al., 2007), these data lend credence to a model in which miR-210 carries a maladaptive role during normoxia, causing a mismatch of…”
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×
“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).”
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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Items 301–400 of 702
Pulmonary Hypertension: Pathophysiology and Signaling Pathways
Maron, B. A., & Loscalzo, J. (2013) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-38664-0_2 · Cited by 41
Self-citationNanotheranostics in Evidence Based Personalized Medicine
SHARMA, S. K. (2014) · Current Drug Targets · doi:10.2174/1389450115666140826123552 · Cited by 40
Prognostic Role of MicroRNA-210 in Various Carcinomas: A Systematic Review and Meta-Analysis
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Hypoxia upregulates the gene expression of mitochondrial aconitase in prostate carcinoma cells
Tsui, K., Chung, L., Wang, S., Feng, T., Chang, P., & Juang, H. (2013) · Journal of Molecular Endocrinology · doi:10.1530/jme-13-0090 · Cited by 41
“2% O2) for 48 h decreased total aconitase activity in primary human pulmonary arterial endothelial cells (Chang et al. 2009).”
BackgroundMicroRNA-210 alleviates oxidative stress-associated cardiomyocyte apoptosis by regulating BNIP3
Diao, H., Liu, B., Shi, Y., Song, C., Guo, Z., Liu, N., Song, X., Lu, Y., Lin, X., & Li, Z. (2017) · Bioscience Biotechnology and Biochemistry · doi:10.1080/09168451.2017.1343118 · Cited by 42
To breathe or not to breathe: the haematopoietic stem/progenitor cells dilemma
Piccoli, C., Agriesti, F., Scrima, R., Falzetti, F., Ianni, M. D., & Capitanio, N. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12253 · Cited by 40
“The notion that a different metabolic profile distinguishes quiescent from differentiating stem cells, with a shift from glycolysis to mitochondrial OXPHOS, is supported by recent experimental results (Simsek et al., 2010; Suda et al., 2011; Takubo et al., 2013).”
BackgroundInfluentialSaumet, A., Vetter, G., Bouttier, M., Antoine, E., Roubert, C., Orsetti, B., Theillet, C. G., & Lecellier, C. (2012) · Molecular BioSystems · doi:10.1039/c2mb25298h · Cited by 39
Wiese, M., Gerlach, R. G., Popp, I., Matuszak, J., Mahapatro, M., Castiglione, K., Chakravortty, D., Willam, C., Hensel, M., Bogdan, C., et al. (2012) · Infection and Immunity · doi:10.1128/iai.05972-11 · Cited by 39
“Mitochondrial activity is impaired under hypoxia (14).”
ResultMiRNA Deregulation in Cardiac Aging and Associated Disorders
Verjans, R., van Bilsen, M., & Schroen, B. L. M. (2017) · International review of cytology · doi:10.1016/bs.ircmb.2017.03.004 · Cited by 39
Rats with a Human Mutation of NFU1 Develop Pulmonary Hypertension
Niihori, M., Eccles, C. A., Kurdyukov, S., Zemskova, M., Varghese, M. V., Степанова, А., Galkin, A. S., Rafikov, R., & Rafikova, O. (2019) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2019-0065oc · Cited by 39
“Chan and colleagues previously reported that hypoxia-mediated repression of ISCU, an Fe-S scaffold protein, attenuates the activity of Fe-S proteins that control mitochondrial metabolism (33).”
BackgroundComplexity and network dynamics in physiological adaptation: An integrated view
Baffy, G., & Loscalzo, J. (2014) · Physiology & Behavior · doi:10.1016/j.physbeh.2014.04.018 · Cited by 40
“Thus, decreased iron-sulfur protein assembly in the electron transport chain mediated by microRNA-210 and dampened flux of the tricarboxylic acid cycle mediated by pyruvate dehydrogenase kinase 1 in response to hypoxia are under the control of hypoxia-inducible factor HIF-1, both mechanisms aimed at reducing mitochond…”
BackgroundSelf-citationTissue-specific changes in fatty acid oxidation in hypoxic heart and skeletal muscle
Morash, A. J., Kotwica, A. O., & Murray, A. J. (2013) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00510.2012 · Cited by 41
“First, iron-sulfur cluster assembly proteins may be subject to ROS-mediated disruption thereby reducing total aconitase protein as suggested by work in various cell lines (7, 11).”
BackgroundMetabolic Roles of HIF1, c-Myc, and p53 in Glioma Cells
Trejo‐Solís, C., Castillo‐Rodríguez, R. A., Serrano-García, N., Silva‐Adaya, D., Vargas-Cruz, S., Chávez-Cortéz, E. G., Gallardo‐Pérez, J. C., Zavala-Vega, S., Cruz-Salgado, A., & Magaña-Maldonado, R. (2024) · Metabolites · doi:10.3390/metabo14050249 · Cited by 41
Renal cell carcinoma: translational aspects of metabolism and therapeutic consequences
Yang, O. C. Y., Maxwell, P. H., & Pollard, P. J. (2013) · Kidney International · doi:10.1038/ki.2013.245 · Cited by 38
Qiu, J., Zhou, X., Zhou, X., Cheng, R., Liu, H., & Li, Y. (2013) · Molecular Medicine Reports · doi:10.3892/mmr.2013.1431 · Cited by 39
Cui, H., Grosso, S., Schelter, F., Mari, B. P., & Krüger, A. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00134 · Cited by 39
“MiR-210 mediates a number of known HIF-1 downstream effects, most importantly the HIF-1 dependent suppression of oxidative phosphorylation (Chan et al., 2011).”
BackgroundmiR-210: a therapeutic target in cancer
Hong, L., Han, Y., Zhang, H., Zhao, Q., & Qiao, Y. (2012) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2012.732066 · Cited by 38
“identified ISCU as targets for repression by miR-210 [58].”
BackgroundMa, Q., Dasgupta, C., Li, Y., Huang, L., & Zhang, L. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1491-8 · Cited by 40
Long Range Endocrine Delivery of Circulating miR-210 to Endothelium Promotes Pulmonary Hypertension
Zhao, J., Florentin, J., Tai, Y., Torrino, S., Ohayon, L., Brzóska, T., Tang, Y. M., Yang, J., Negi, V., Woodcock, C.-. C., et al. (2020) · Circulation Research · doi:10.1161/circresaha.119.316398 · Cited by 38
Self-citationThe myriad essential roles of microRNAs in cardiovascular homeostasis and disease
Neppl, R. L., & Wang, D. (2014) · Genes & Diseases · doi:10.1016/j.gendis.2014.06.003 · Cited by 36
“Perhaps most interestingly, miR-210 was shown to directly repress ISCU1/2, thereby reducing iron-sulfur cluster formation and mitochondrial function via Complex I and aconitase.(236) In addition, HIF-1 signaling is known to i) induce multiple genes involved in glucose transport and glycolysis, ii) enhance the expressi…”
BackgroundSala, V., Bergerone, S., Gatti, S., Gallo, S., Ponzetto, A., Ponzetto, C., & Crepaldi, T. (2013) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-013-1504-0 · Cited by 37
“Furthermore, miR-210 regulates mitochondrial metabolism by targeting crucial proteins of the electron transport chain, at least in cancer cells [66–68].”
BackgroundHypoxia-induced miR-210 modulates the inflammatory response and fibrosis upon acute ischemia
Zaccagnini, G., Greco, S., Longo, M., Maimone, B., Voellenkle, C., Fuschi, P., Carrara, M., Creo, P., Maselli, D., Tirone, M., et al. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03713-9 · Cited by 37
Small Players With Big Roles: MicroRNAs as Targets to Inhibit Breast Cancer Progression
Greene, S. B., Herschkowitz, J. I., & Rosen, J. M. (2010) · Current Drug Targets · doi:10.2174/138945010792006762 · Cited by 39
“Further analysis found that miR-210 targets the iron-sulfur cluster assembly proteins ISCU1/2, and this may affect downstream metabolic functions, such as reduced ATP generation, elevated glycolysis, and mitochondrial metabolism [121].”
BackgroundTaylor, D. F., & Bishop, D. J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031517 · Cited by 37
Riou, M., Enache, I., Sauer, F., Charles, A., & Gény, B. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119572 · Cited by 38
“Furthermore, one of the mechanisms of hypoxia-inducible microRNA-210 (mir-210) in the physiopathology of PAH is thought to be the repression of the assembly of Fe–S clusters [82,83].”
BackgroundFernandes, J. L., Martins, F. O., Olea, E., Prieto‐Lloret, J., Braga, P. C., Sacramento, J. F., Sequeira, C. O., Negrinho, A. P., Pereira, S. A., Alves, M. G., et al. (2023) · Antioxidants · doi:10.3390/antiox12111910 · Cited by 38
“This result agrees with the available literature [50,51].”
The Role of Hypoxia Regulated microRNAs in Cancer
McCormick, R., Buffa, F. M., Ragoussis, J., & Harris, A. L. (2010) · Current topics in microbiology and immunology · doi:10.1007/82_2010_76 · Cited by 37
“2010), which was confirmed by experimental validation both in cancer and normal tissues (Chan et al. 2009).”
BackgroundMethodInfluentialBrevik, A., Lindeman, B., Brunborg, G., & Duale, N. (2012) · International Journal of Cell Biology · doi:10.1155/2012/407431 · Cited by 37
“The iron-sulfur cluster assembly proteins ISCU1 and ISCU2 have been identified as direct targets for miR-210 in human lung endothelial cells [62].”
BackgroundMicroRNA-146b inhibition augments hypoxia-induced cardiomyocyte apoptosis
Li, J., He, S., Feng, Z., Zhao, L., Jia, W., Liu, P., Zhu, Y. K., Zhao, J. H., & XIAO, Y.-B. (2015) · Molecular Medicine Reports · doi:10.3892/mmr.2015.4333 · Cited by 36
“Furthermore, the expression of miR-146b also increased in human pulmonary arterial smooth muscle cells following the onset of hypoxia (7), and the levels of miR-146b were increased in the lung tissue in an experimental animal model of CHD compared with that of the control groups (8).”
InfluentialProtection of Human Umbilical Vein Endothelial Cells against Oxidative Stress by MicroRNA‐210
Li, T., Song, X., Zhang, J., Zhao, L., Shi, Y., Li, Z., Liu, J., Liu, N., Yan, Y., Xiao, Y., et al. (2017) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2017/3565613 · Cited by 36
“HUVECswere treatedwith different concentrations of hydrogen peroxide (H 2 O 2 ), and cell viability was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and ATP assay.”
MethodMitochondrial miRNAs in diabetes: just the tip of the iceberg
Baradan, R., Hollander, J. M., & Das, S. (2017) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2016-0580 · Cited by 36
Houri, K., Mori, T., Onodera, Y., Tsujimoto, T., Takehara, T., Nakao, S., Teramura, T., & Fukuda, K. (2020) · Scientific Reports · doi:10.1038/s41598-020-60346-2 · Cited by 37
Beyond mitochondria: Alternative energy-producing pathways from all strata of life
Auger, C., Vinaik, R., Appanna, V. D., & Jeschke, M. G. (2021) · Metabolism · doi:10.1016/j.metabol.2021.154733 · Cited by 36
MicroRNA regulation of cancer metabolism: role in tumour suppression
Tomasetti, M., Santarelli, L., Neužil, J., & Dong, L. (2014) · Mitochondrion · doi:10.1016/j.mito.2014.06.004 · Cited by 36
“homeostasis (Chan et al., 2012).”
Ferecatu, I., Canal, F., Fabbri, L., Mazure, N. M., Bouton, C., & Golinelli‐Cohen, M. (2018) · PLoS ONE · doi:10.1371/journal.pone.0194782 · Cited by 34
Vogel, J., Niederer, D., Engeroff, T., Vogt, L., Troidl, C., Schmitz‐Rixen, T., Banzer, W. B., & Troidl, K. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20133249 · Cited by 35
Clinical value of non-coding RNAs in cardiovascular, pulmonary, and muscle diseases
Bonnet, S., Boucherat, O., Paulin, R., Wu, D., Hindmarch, C. C. T., Archer, S. L., Song, R., Moore, J. B., Provencher, S., Zhang, L., et al. (2019) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00078.2019 · Cited by 34
Bose, M., Chatterjee, S., Chakrabarty, Y., Barman, B., & Bhattacharyya, S. N. (2020) · Life Science Alliance · doi:10.26508/lsa.201800161 · Cited by 35
“It has been shown earlier that the metabolic flux is controlled by mitochondria, and that the same is also controlled by miRNAs (33, 34).”
BackgroundComputational repurposing of therapeutic small molecules from cancer to pulmonary hypertension
Negi, V., Yang, J., Speyer, G., Pulgarin, A., Handen, A. L., Zhao, J., Tai, Y., Tang, Y., Culley, M. K., Yu, Q., et al. (2021) · Science Advances · doi:10.1126/sciadv.abh3794 · Cited by 35
“Because ISCU was predicted as a central mediator in C43 rewiring by BRD2889 and prior studies have demonstrated that hypoxia-dependent endothelial ISCU deficiency promotes PH via repressing iron sulfur– dependent mitochondrial metabolism (23, 37), we focused on endothelial cells exposed to hypoxia to define this putat…”
BackgroundSelf-citationMicroRNA-210 promotes sensory axon regeneration of adult mice in vivo and in vitro
Hu, Y., Jiang, J., Yan-Gao, Wang, R., & Tu, G. (2016) · Neuroscience Letters · doi:10.1016/j.neulet.2016.04.034 · Cited by 35
Gestational hypoxia and epigenetic programming of brain development disorders
Ma, Q., Xiong, F., & Zhang, L. (2014) · Drug Discovery Today · doi:10.1016/j.drudis.2014.09.010 · Cited by 33
“Recently, miR-210 has been suggested as a new player in regulating mitochondrial metabolism under hypoxia, through repressing the expression of iron-sulfur (FeS) cluster scaffold protein isoforms ISCU1 and ISCU2 [91] that facilitate the assembly of [4Fe-4S] and [2Fe-2S] iron-sulfur clusters.”
Background“Seed-Milarity” Confers to hsa-miR-210 and hsa-miR-147b Similar Functional Activity
Bertero, T., Grosso, S., Robbe-Sermesant, K., Lebrigand, K., Hénaoui, I. S., Puisségur, M.-P., Fourré, S., Zaragosi, L., Mazure, N. M., Ponzio, G., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044919 · Cited by 36
“This effect could be likely mediated by the targeting of several mitochondrial components by these 2 miRNAs, such as ISCU, NDUFA4 or SDHD, inducing mitochondrial dysfunctions associated with induction of reactive oxygen species, decrease of mitochondrial membrane potential and caspase-3 activation [26,43,44].”
BackgroundPrognostic Impact of Hypoxia-InduciblemiRNA-210in Patients with Lung Adenocarcinoma
Osugi, J., Kimura, Y., Owada, Y., Inoue, T., Watanabe, Y., Yamaura, T., Fukuhara, M., Muto, S., Okabe, N., Matsumura, Y., et al. (2015) · Journal of Oncology · doi:10.1155/2015/316745 · Cited by 34
“HIF-1𝛽 is a non-oxygen-responsive nuclear protein.”
Adaptions to Hypoxia and Redox Stress
Loscalzo, J. (2016) · Circulation Research · doi:10.1161/circresaha.116.309394 · Cited by 34
“(4) There is compartmental heterogeneity in the distribution of ROS within the cell.”
Self-citationYardeni, T., Fine, R., Joshi, Y., Gradus, T., Kozer, N., Reichenstein, I., Yanowski, E., Nevo, S., Weiss-Tishler, H., Eisenberg‐Bord, M., et al. (2018) · Scientific Reports · doi:10.1038/s41598-017-17878-x · Cited by 34
Tong, W.-H., Maio, N., Zhang, D., Palmieri, E. M., Ollivierre, H., Ghosh, M. C., McVicar, D. W., & Rouault, T. A. (2018) · Blood Advances · doi:10.1182/bloodadvances.2018015669 · Cited by 36
“ISCU transcripts have previously been found to be the targets of miR210, which is induced by HIF-1a.(30) Therefore, we asked whether activation of HIF-1a (Figure 2A) decreased ISCU in LPS/IFNg–activated cells.”
BackgroundCarré, J. L., Lamon, S., & Léger, B. (2014) · Frontiers in Genetics · doi:10.3389/fgene.2014.00413 · Cited by 34
Toghiani, R., Azimian, V., Najafi, H., Mirian, M., Azarpira, N., Abolmaali, S. S., Varshosaz, J., & Tamaddon, A. M. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-024-03845-7 · Cited by 34
“A diverse range of targets regulated by miR-210 have been implicated in mitochondrial metabolism [62], oxidative stress responses [63], cell proliferation [64], and regulating cell death or apoptosis [65].”
BackgroundHu, X., Song, R., & Zhang, L. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/9194269 · Cited by 36
“The downregulation of iron-sulfur cluster assembly enzyme (ISCU) in mitochondria by miR-210 in hypoxia would block electron exit from complex I, promoting its leakage to generation of ROS [219].”
BackgroundMolecular Mechanisms and Epigenetic Regulation in Diabetic Cardiomyopathy
Mittal, A., Garg, R., Bahl, A., & Khullar, M. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.725532 · Cited by 34
“miRNA-210 is a direct regulator of ISCU1/2, iron sulfur complex protein, which drives the electron transport chain (ETC) by regulating the function of aconitase and complex I (107).”
BackgroundTherapeutic Potential of Modulating MicroRNA in Peripheral Artery Disease
Hamburg, N. M., & Leeper, N. J. (2014) · Current Vascular Pharmacology · doi:10.2174/15701611113119990014 · Cited by 35
“[89,90] MiR-210 expression, in the setting of hypoxia, augments the angiogenic response to Hamburg and Leeper Page 6”
BackgroundSáenz‐de‐Santa‐María, I., Bernardo‐Castiñeira, C., Secades, P., Fernández, S. B. D. Q., Rodrigo, J. P., Astudillo, A., & Chiara, M. (2017) · Oncotarget · doi:10.18632/oncotarget.14629 · Cited by 32
MicroRNAs in Pulmonary Hypertension, from Pathogenesis to Diagnosis and Treatment
Xu, J., Linneman, J., Zhong, Y., Yin, H., Xia, Q., Kang, K., & Gou, D. (2022) · Biomolecules · doi:10.3390/biom12040496 · Cited by 34
MicroRNAs as Regulators of Cancer Cell Energy Metabolism
Natarajaseenivasan, S. M., Velusamy, P., Mercy, C. S. A., Langford, D., Natarajaseenivasan, K., & Shanmughapriya, S. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12081329 · Cited by 35
“Another miRNA, miR-210, specifically induced by HIF-1α, represses the iron-sulfur cluster assembly proteins (ISCU1/2) [89].”
BackgroundThe Search for Disease-Modifying Therapies in Pulmonary Hypertension
Woodcock, C.-. C., & Chan, S. Y. (2019) · Journal of Cardiovascular Pharmacology and Therapeutics · doi:10.1177/1074248419829172 · Cited by 31
“phosphorylation and electron transport, has been causatively linked to PH via both genetic and acquired triggers.(216,217) Clinical trials are currently ongoing to evaluate whether iron supplementation can improve manifestations of PAH (NCT03371173).”
Self-citationWalsh, H. R., Cruickshank, B. M., Brown, J. M., & Marcato, P. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00753 · Cited by 33
“For example, hypoxia-induced miR210 reduces mitochondrial respiration in cancer cells, including breast cancer (57).”
BackgroundHe, M., Zhou, C., Lu, Y., Mao, L., Xi, Y., Mei, X., Wang, X. B., Zhang, L., Yu, Z., & Zhou, Z. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/5406284 · Cited by 31
“Colorimetric assay-based typical FeS metabolic enzyme measurements were performed as in a previous study [8].”
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“S bio-synthesis in the enhanced mitochondrial functions in tumor cells; however, IscU2 suppression was found to be able to decrease the activity of mitochondrial complex I and force an adaption to hypoxia in breast cancer cells 22,35 .”
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“HK1, HK2, and GPI are essential enzymes in glycolysis while LDHA and PDK1 decide which way pyruvate goes to, indicating that miR-34a cannot only suppress cancer by down-regulating aerobic glycolysis but can also mediate metabolic switch from glycolysis to OXPHOS, which provides a therapeutic target to cancer cells (Ta…”
BackgroundInfluentialMicroRNAs: are they the missing link between hypoxia and pre-eclampsia?
Li, J. Y. Z., Yong, T. Y., Michael, M., & Gleadle, J. (2013) · Hypertension in Pregnancy · doi:10.3109/10641955.2013.832772 · Cited by 30
“It has been hypothesized that miR-210 represses the expression of ISCU during hypoxic conditions, thus disrupting mitochondrial function (47).”
BackgroundYang, W., Wei, J., Sun, T., & Liu, F. (2013) · Radiation Oncology · doi:10.1186/1748-717x-8-102 · Cited by 30
“EFNA3 is an ephrin family member involving vascular development [29].”
BackgroundInfluentialNoncoding RNAs in the Vascular System Response to Oxidative Stress
Fuschi, P., Maimone, B., Gaetano, C., & Martelli, F. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7229 · Cited by 31
“In particular, miR-210 directly inhibits the expression of ISCU1/2 (22, 43, 44, 61), necessary for the assembly of Fe-S clusters that are present in several ETC and TCA cycle components (170).”
InfluentialMicroRNA‐210 Decreases heme Levels by Targeting Ferrochelatase in Cardiomyocytes
Qiao, A., Khechaduri, A., Mutharasan, R. K., Wu, R., Nagpal, V., & Ardehali, H. (2013) · Journal of the American Heart Association · doi:10.1161/jaha.113.000121 · Cited by 31
“We then transfected H9c2 cells with an ISCU construct lacking the 3′ UTR, rendering it unresponsive to miR-210 (Figure 9C).(11) Treatment of cells with pre-miR–210 increased the levels of miR-210 irrespective of ISCU overexpression (202 42 for GFP transfected cells and 827 129 for ISCU1+ISCU2 transfected cells).”
MethodAmbrose, L. J. A., Jamil, A. H. A., Gomes, R. S. M., Carter, E. E., Carr, C. A., Clarke, K., & Heather, L. C. (2014) · Journal of Cardiovascular Pharmacology and Therapeutics · doi:10.1177/1074248414524480 · Cited by 30
HIF1α-dependent uncoupling of glycolysis suppresses tumor cell proliferation
Urrutia, A. A., Mesa‐Ciller, C., Guajardo-Grence, A., Alkan, H. F., Soro-Arnáiz, I., Vandekeere, A., Campos, A. M. F., Igelmann, S., Fernández-Arroyo, L., Rinaldi, G., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114103 · Cited by 31
microRNAs Tune Oxidative Stress in Cancer Therapeutic Tolerance and Resistance
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“miR-210 activates generation of ROSs [145] via suppressing iron–sulfur cluster assembly enzyme [146,147] and cytochrome c oxidase assembly protein [148] in the mitochondria electron transport chain and the TCA cycle.”
BackgroundDefective mitochondrial ISCs biogenesis switches on IRP1 to fine tune selective mitophagy
Wu, H., Wei, H., Zhang, D., Sehgal, S. A., Zhang, D., Wang, X., Qin, Y., Liu, L., & Chen, Q. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101661 · Cited by 30
“It is reasonable that defective ISCs assembly leading to disturbed mitochondrial bioenergetics results in Warburg effect in cancer cells [52].”
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Cell death or survival: Insights into the role of mRNA translational control
Bhatter, N., Dmitriev, S. E., & Ivanov, P. V. (2023) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2023.06.006 · Cited by 31
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“Expression of the COX10 gene is regulated by the microRNA miR-210, which is induced under hypoxia or Fe deficiency in order to reduce COX10 levels and thus regulates the rate of oxygen consumption and mitochondrial metabolism (Chan et al. , 2009).”
Insights into the post-transcriptional regulation of the mitochondrial electron transport chain
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Metabolite and protein shifts in mature erythrocyte under hypoxia
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Self-citationMammalian Target of Rapamycin Complex 1 (mTORC1)-mediated Phosphorylation Stabilizes ISCU Protein
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Zarrabi, A. J., Kao, D. D., Nguyen, D. T., Loscalzo, J., & Handy, D. E. (2017) · Cellular Signalling · doi:10.1016/j.cellsig.2017.07.008 · Cited by 28
“HIF-dependent actions, such as the regulation of specific miRNAs (hypoxamirs), coordinate the hypoxia-mediated decrease in electron transport with the reduced availability of molecular oxygen [4,5].”
InfluentialSelf-citationRegulation of iron homeostasis by microRNAs
Castoldi, M., & Muckenthaler, M. U. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1031-4 · Cited by 30
Ajuwon, O. R., Marnewick, J. L., & Davids, L. M. (2015) · InTech eBooks · doi:10.5772/61614 · Cited by 31
“Other studies have also shown that HIF-1α regulates the expression of certain cytochrome components directly and also regulates specific microRNAs that in turn regulate the expression of components of the electron transport chain [10,39,40].”
BackgroundMitochondrial-related microRNAs and their roles in cellular senescence
Luo, L., An, X., Xiao, Y., Sun, X., Li, S., Wang, Y., Sun, W., & Yu, D. (2024) · Frontiers in Physiology · doi:10.3389/fphys.2023.1279548 · Cited by 30
Hypoxia-Induced miR-210 Is Necessary for Vascular Regeneration upon Acute Limb Ischemia
Zaccagnini, G., Maimone, B., Fuschi, P., Longo, M., Silva, D. D., Carrara, M., Voellenkle, C., Perani, L., Esposito, A., Gaetano, C., et al. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms21010129 · Cited by 27
“Moreover, many terms were related to metabolism and mitochondrial organization, consistent with the role of miR-210 in the regulation of oxidative phosphorylation [5,7,14].”
BackgroundThe pivotal role of MicroRNAs in glucose metabolism in cancer
Taefehshokr, S., Taefehshokr, N., Hemmat, N., Hajazimian, S., Isazadeh, A., Dadebighlu, P., & Baradaran, B. (2020) · Pathology - Research and Practice · doi:10.1016/j.prp.2020.153314 · Cited by 29
Kynurenine induces an age-related phenotype in bone marrow stromal cells
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Hypoxamirs and Mitochondrial Metabolism
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“Expression profiling has demonstrated a wide range of miRNA whose expression is altered under hypoxia, in both primary (14, 27) and transformed (11, 33, 36, 52) cell types, although the results can be quite tissue specific.”
BackgroundResultInfluentialSelf-citationStudying the association of micro RNA ‐210 level with chronic hepatitis B progression
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“Of note, several other miRNAs linked to iron uptake and metabolism were dysregulated after stimulation with both IS and IIM, such as miR-320 [53] and miR-210 [54, 55].”
BackgroundThe Favored Mechanism for Coping with Acute Cold Stress: Upregulation of miR-210 in Rats
Guo, W., Lian, S., Li, Z., Zang, S., Chen, Y., Lang, L., Xu, B., Guo, J., Ji, H. L., Wang, J., et al. (2018) · Cellular Physiology and Biochemistry · doi:10.1159/000489449 · Cited by 26
The molecular rationale for therapeutic targeting of glutamine metabolism in pulmonary hypertension
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“However, via chronically repressing ISCU1/2 and Fe-S biogenesis, miR-210 acts as an intracellular pathogenic factor in pulmonary arterial cells to induce oxidative stress and to promote PH in vivo.”
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Altered Gene Expression Associated with microRNA Binding Site Polymorphisms
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“As the site is covered by AGO-CLIP reads and targeting is experimentally well validated [44–46,67], we have reason to believe that this miRNA activity may be the underlying cause of the observed cis-eQTL effect.”
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“, 2007), and its strikingly robust induction by hypoxia across multiple mammalian cell types is unique among all HIF-dependent miRNAs (Chan et al., 2009).”
Mechanisms Contributing to the Dysregulation of miRNA-124 in Pulmonary Hypertension
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“expression of miR-210 has been reported in hypoxia induced pulmonary arterial ECs and SMCs and were shown to play an important role in PH through repression of mitochondrial respiration during hypoxia [28,29].”
Giordani, C., Silvestrini, A., Giuliani, A., Olivieri, F., & Rippo, M. R. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.734976 · Cited by 25
A narrative review of research advances in hypoxic pulmonary hypertension
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“It is also a direct inhibitory target of hypoxia-induced MIR-210 (40).”
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Harnessing bioactive nanomaterials in modulating tumor glycolysis-associated metabolism
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“Hypoxia-induced miR-210 is essential for cell survival during acute hypoxic stress by downregulating the iron sulfur complex assembly proteins 1/2 (Chan et al., 2009) and additional mitochondrial electron transport proteins (Muralimanoharan et al., 2012; Puiss egur et al., 2011), however, which…”
BackgroundShvetsova, A., Mennerich, D., Kerätär, J. M., Hiltunen, J. K., & Kietzmann, T. (2017) · Redox Biology · doi:10.1016/j.redox.2017.05.003 · Cited by 24
The Role of Reductive Stress in the Pathogenesis of Endocrine-Related Metabolic Diseases and Cancer
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“Hypoxia suppresses the expression of iron–sulfur cluster scaffold proteins, reducing the activity of mitochondrial ETC complexes I, II, and III, which contributes to NADH accumulation [124].”
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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