MicroRNA-210 Controls Mitochondrial Metabolism during Hypoxia by Repressing the Iron-Sulfur Cluster Assembly Proteins ISCU1/2 |
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Authors: | Stephen Y Chan Ying-Yi Zhang Craig Hemann Christopher E Mahoney Jay L Zweier Joseph Loscalzo |
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Institution: | 1Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA;2Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA;3Harvard Medical School, Boston, MA 02115, USA;4Department of Medicine, Ohio State University, Columbus, OH 43210, USA |
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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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Keywords: | HUMDISEASE |
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