Genetic and hypoxic alterations of the micro RNA ‐210‐ ISCU 1/2 axis promote iron–sulfur deficiency and pulmonary hypertension

Abstract

Iron–sulfur (Fe-S) clusters are essential for mitochondrial metabolism, but their regulation in pulmonary hypertension (PH) remains enigmatic. We demonstrate that alterations of the miR-210-ISCU1/2 axis cause Fe-S deficiencies in vivo and promote PH. In pulmonary vascular cells and particularly endothelium, hypoxic induction of miR-210 and repression of the miR-210 targets ISCU1/2 down-regulated Fe-S levels. In mouse and human vascular and endothelial tissue affected by PH, miR-210 was elevated accompanied by decreased ISCU1/2 and Fe-S integrity. In mice, miR-210 repressed ISCU1/2 and promoted PH. Mice deficient in miR-210, via genetic/pharmacologic means or via an endothelial-specific manner, displayed increased ISCU1/2 and were resistant to Fe-S-dependent pathophenotypes and PH. Similar to hypoxia or miR-210 overexpression, ISCU1/2 knockdown also promoted PH. Finally, cardiopulmonary exercise testing of a woman with homozygous ISCU mutations revealed exercise-induced pulmonary vascular dysfunction. Thus, driven by acquired (hypoxia) or genetic causes, the miR-210-ISCU1/2 regulatory axis is a pathogenic lynchpin causing Fe-S deficiency and PH. These findings carry broad translational implications for defining the metabolic origins of PH and potentially other metabolic diseases sharing similar underpinnings.

Translational Advances in the Field of Pulmonary Hypertension.Translating MicroRNA Biology in Pulmonary Hypertension. It Will Take More Than “miR” Words

“…Dysregulation of entire sets of circulating miRNAs in PAH has also been described (74,76). Other miRNAs with known causative actions in PAH, such as the miR-130/301 family (20) and miR-210 (14), have been found to be elevated in the pulmonary circulation of patients with PH. Moreover, differential expression of plasma miRNAs was also reported in acute pulmonary embolism (77) and chronic thromboembolic PH (78).…”

“…Among its pleiotropic actions, miR-210 was found to repress directly the iron-sulfur cluster assembly proteins (ISCU1/2) essential for mitochondrial respiration, leading to Fe-S deficiencies and PH development. Accordingly, forced expression of miR-210 was sufficient to induce pulmonary vascular dysfunction in mice, whereas molecular or genetic inhibition of miR-210 prevented and reversed chronic hypoxic PH (14).…”

“…In many regards, PH disease progression mirrors tumorigenesis in relying on a metabolic switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis (known as the Warburg effect) (2) to provide a survival advantage to highly proliferating cells (11). The hypoxia-dependent miR-210 is one of several miRNAs implicated in this metabolic rewiring (12)(13)(14). Among its pleiotropic actions, miR-210 was found to repress directly the iron-sulfur cluster assembly proteins (ISCU1/2) essential for mitochondrial respiration, leading to Fe-S deficiencies and PH development.…”

Mitochondria in lung disease

“…Mitochondria are key regulators of the second messengers calcium (Ca 2+ ) and iron (Fe), which control a diverse range of cellular processes, including mROS production. The formation of mitochondrial iron-sulfur (Fe-S) clusters is essential for many of the ETC complexes (complexes I and II) and other enzymes important for mitochondrial metabolism (75). Similarly, Ca 2+ mobilization and the activation of Ca…”

Discerning functional hierarchies of microRNAs in pulmonary hypertension

“…miR-210 was found to have substantial pleiotropic function in mitochondrial metabolism (45), proliferation (53,54), and cell survival, thus promoting vascular remodeling and PH in vivo (55). miR-210 is also released into the extracellular space and may function as an endocrine or paracrine messenger of hypoxic stress among anatomically distinct tissues (56).…”