Jin Zhang , Yanhong Zhang , Shakur Mohibi , Vivian Perng , Miranda Bustamante , Yang Shi , Kenichi Nakajima , Mingyi Chen , Xinbin Chen
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引用次数: 0
Abstract
Ferredoxin 1 and 2 (FDX1/2) constitute an evolutionarily conserved FDX family of iron-sulfur cluster–containing proteins. FDX1/2 are cognate substrates of ferredoxin reductase and serve as conduits for electron transfer from NADPH to a set of proteins involved in biogenesis of corticosteroids, hemes, iron-sulfur cluster, and lipoylated proteins. Fdx1 is essential for embryonic development and lipid homeostasis. Herein, Fdx2-deficient mice were generated to explore the physiological role of FDX2. Interestingly, unlike Fdx1-null embryos, which were dead at embryonic day 10.5 to 13.5, Fdx2-null mice were viable. Both Fdx2-null and Fdx2-heterozygous mice had a short lifespan and were susceptible to spontaneous tumors and steatohepatitis. Moreover, FDX2 deficiency increased, whereas overexpression of FDX2 decreased cytoplasmic accumulation of lipid droplets. Consistently, FDX2 deficiency led to accumulation of cholesterol and triglycerides. Mechanistically, FDX2 deficiency suppressed expression of cholesterol transporter ATP-binding cassette transporter A1 (ABCA1) and activated master lipid transcription regulators sterol regulatory element-binding proteins 1/2, thus leading to altered lipid metabolism. Untargeted lipidomic analysis showed that FDX2 deficiency led to altered biosynthesis of various lipid classes, including cardiolipins, cholesterol, ceramides, triglycerides, and fatty acids. In summary, these findings underline an indispensable role of FDX2 in tumor suppression and lipid homeostasis at both cellular and organismal levels without being a prerequisite for embryonic development.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.