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Pseudouracil is the most prevalent RNA modification with aberrant functions that have been implicated in a variety of human diseases. However, the specific effects of pseudouracil on hematopoiesis are still poorly understood.
On April 18, 2024, Jun Shi, Yajing Chu and Weiping Yuan jointly published a research paper entitled "Mitochondrial tRNA pseudouridylation governs erythropoiesis" in BloodOnline, which revealed the role of tRNA pseudouracil in erythropoiesis and its association with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia ( MLASA).
Pseudouracil is the most abundant RNA modification of tRNA, rRNA, and mRNA. It plays a vital role in RNA biology, influencing processes such as protein translation, mRNA precursor processing, and various cellular functions. Pseudouracil refers to the conversion of uracil (U) to pseudouracil (Ψ) catalyzed by pseudouracil synthetases (PUSs). Aberrant pseudouracil has been implicated in several human diseases, such as PUS7-mediated pseudouracil in stem cell commitment, leukemia development, and glioblastoma. Red blood cell production is a complex process with different stages, and any disturbance can lead to anemia. Sideroblastic anemia (SA) is an anemia characterized by ring-shaped sideroblasts. The pathogenic genes LARS2, ABCB7 and ALAS2 of congenital sideroblastic anemia (CSA) are mainly involved in mitochondrial pathways such as heme biosynthesis, iron-sulfur mass biogenesis, mitochondrial translation and respiration, suggesting that anemia is related to mitochondria. A rare form of SA, known as mitochondrial myopathy, lactic acidosis, and sideroblastic anemia (MLASA), involves multisystem defects and is associated with mutations in three genes: pseudouracil synthetase 1 (PUS1), mitochondrial tyrosine tRNA synthetase (YARS2), and MT-ATP6 gene. PUS1 was the first gene to be found to be associated with MLASA, but the role of PUS1 in erythropoiesis remains unclear.
模式图（Credit: Blood）
The study confirmed impaired red blood cell function in MLASA iPSCs and anemia in a mouse model of MLASA by using patient-specific induced pluripotent stem cells (iPSCs) harboring PUS1 gene mutations and corresponding mutant mouse models. Both MLASA-induced pluripotent stem cells and mouse red milk cells exhibit impaired mitochondrial function and impaired protein synthesis. Mechanistically, PUS1 deficiency leads to pseudouracil loss, resulting in decreased mitochondrial tRNA levels, resulting in abnormal mitochondrial translation. Screening mitochondrial supplements designed to enhance respiratory or heme synthesis has a limited effect on promoting red blood cell differentiation. Interestingly, the mTOR inhibitor rapamycin promotes erythroid differentiation of MLASA-iPSCs by inhibiting mTOR signaling and protein synthesis, and consistent results have been observed in mouse models of MLASA. Importantly, rapamycin treatment was effective in improving the anemia phenotype in MLASA patients. The study provides new insights into the critical role of mitochondrial tRNA pseudouracil in controlling erythropoiesis and a potential therapeutic strategy for anemia patients facing challenges related to protein translation.
Original link https://doi.org/10.1182/blood.2023022004
Editor-in-charge|Explore Jun
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文章来源|“ iNature"
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