MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2

Chan SY, Zhang YY, Hemann C, Mahoney CE, Zweier JL, Loscalzo J
Source: Cell Metab
Publication Date: (2009)
Issue: 10(4): 273-84
Research Area:
Basic Research
Cells used in publication:
SMC, pul.artery (PASMC), human
Species: human
Tissue Origin: artery
Endothelial, pulmonary artery (HPAEC), human
Species: human
Tissue Origin: artery
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.