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Editorial
. 2020 Feb;62(2):136-138.
doi: 10.1165/rcmb.2019-0309ED.

NFU1, Iron-Sulfur Biogenesis, and Pulmonary Arterial Hypertension: A (Metabolic) Shift in Our Thinking

Miranda K Culley  1   2 , Dror Perk  1   2 , Stephen Y Chan  1   2
Affiliations
Editorial

NFU1, Iron-Sulfur Biogenesis, and Pulmonary Arterial Hypertension: A (Metabolic) Shift in Our Thinking

Miranda K Culley et al. Am J Respir Cell Mol Biol. 2020 Feb.
No abstract available

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Figures

Figure 1.
Figure 1.
Human mutation of the iron-sulfur (Fe-S) scaffolding gene NFU1 in rats drives sex-dependent metabolic changes and pulmonary arterial hypertension (PAH). NFU1 is a mitochondrial scaffolding protein that is involved in the multistep process of Fe-S biosynthesis, and genetic mutation in patients with mitochondrial multiple dysfunctions syndrome 1 (MMDS1) has previously been associated with pulmonary hypertension. Niihori and colleagues used CRISPR/Cas9 to generate human missense mutations in Sprague Dawley rats (16). In female homozygous rats, they observed mitochondrial deficiencies in electron transport chain complexes I and II, and increased right ventricular systolic pressure and right ventricular hypertrophy. Although certain metabolic phenotypic aberrations persisted, male homozygous rats exhibited compensatory mechanisms that seemed to prevent or delay disease formation. Although the complete mechanism that accounts for this sex dimorphism is not yet clear, these data demonstrate that the NFU1 mutation is a primary driver of pulmonary vascular disease, supporting the classification of Fe-S genetic mutations into heritable causes of WHO Group 1 PAH, bolstering the use of emerging metabolic therapies in PAH, and informing the diagnostic and prognostic benefits of sex-driven differences in metabolism. BOLA3 = BolA family member 3; CIA = cytoplasmic iron-sulfur assembly; Core ISC = core iron-sulfur cluster machinery; ISCU = iron-sulfur duster assembly protein; KGDH = α-ketoglutarate dehydrogenase; LA = lipoic acid; LIAS = lipoic acid synthetase; NFS1 = a mitochondrial cysteine desulfurase; NFU1 = mitochondrial iron-sulfur scaffold; PDH = pyruvate dehydrogenase. Illustration by Jill K. Gregory.
See this image and copyright information in PMC

Comment on

  • Rats with a Human Mutation of NFU1 Develop Pulmonary Hypertension.
    Niihori M, Eccles CA, Kurdyukov S, Zemskova M, Varghese MV, Stepanova AA, Galkin A, Rafikov R, Rafikova O. Niihori M, et al. Am J Respir Cell Mol Biol. 2020 Feb;62(2):231-242. doi: 10.1165/rcmb.2019-0065OC. Am J Respir Cell Mol Biol. 2020. PMID: 31461310 Free PMC article.

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