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

By S. Y. Chan, Ying‐yi Zhang, C. Hemann, Christopher E. Mahoney, Jay L. Zweier, Joseph Loscalzo. Cell Metabolism, 2009

664 citations recorded by the source corpus.

Summary 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 up-regulating 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.

Subfields: Cancer Research, Molecular Biology, Renewable Energy, Sustainability and the Environment

View Paper: https://www.semanticscholar.org/paper/3353dbee8a539259459cd0c12480a5db76fbeef9

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Citations in the corpus

ADAPTIVE AND MALADAPTIVE CARDIORESPIRATORY RESPONSES TO CONTINUOUS AND INTERMITTENT HYPOXIA MEDIATED BY HYPOXIA-INDUCIBLE FACTORS 1 AND 2 (2012, background): “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 ”
MicroRNA Functions in Stress Responses (2010, positive): “…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).”
The Warburg effect in tumor progression: Mitochondrial oxidative metabolism as an anti-metastasis mechanism (2014, background): “Consequently, miR-210 disrupts the integrity of iron-sulfur clusters and represses mitochondrial respiration [66].”
Mitochondrial reactive oxygen species and cancer (2014, background): “HIF1α has also been shown to induce microRNA210, which is sufficient to decrease expression of the ironsulfur cluster assembly proteins ISCU1/2 and decrease mitochondrial oxygen consumption, increase lactate production, and increase ROS [62,63].”
HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. (2013, positive): “Among the targets of miR-210 that are downregulated in hypoxic cells are mRNAs encoded by the ISCU gene, which encodes an iron-sulfur cluster assembly enzyme that is required for the activity of mitochondrial electron transport complex I (41, 42).”