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Chemical reversal of abnormalities in cells carrying mitochondrial DNA mutations.

携带线粒体DNA突变的细胞中异常的化学逆转。

  • 影响因子:9.33
  • DOI:10.1038/s41589-020-00676-4
  • 作者列表:"Kobayashi H","Hatakeyama H","Nishimura H","Yokota M","Suzuki S","Tomabechi Y","Shirouzu M","Osada H","Mimaki M","Goto YI","Yoshida M
  • 发表时间:2021-03-01
Abstract

:Mitochondrial DNA (mtDNA) mutations are the major cause of mitochondrial diseases. Cells harboring disease-related mtDNA mutations exhibit various phenotypic abnormalities, such as reduced respiration and elevated lactic acid production. Induced pluripotent stem cell (iPSC) lines derived from patients with mitochondrial disease, with high proportions of mutated mtDNA, exhibit defects in maturation into neurons or cardiomyocytes. In this study, we have discovered a small-molecule compound, which we name tryptolinamide (TLAM), that activates mitochondrial respiration in cybrids generated from patient-derived mitochondria and fibroblasts from patient-derived iPSCs. We found that TLAM inhibits phosphofructokinase-1 (PFK1), which in turn activates AMPK-mediated fatty-acid oxidation to promote oxidative phosphorylation, and redirects carbon flow from glycolysis toward the pentose phosphate pathway to reinforce anti-oxidative potential. Finally, we found that TLAM rescued the defect in neuronal differentiation of iPSCs carrying a high ratio of mutant mtDNA, suggesting that PFK1 represents a potential therapeutic target for mitochondrial diseases.

摘要

: 线粒体DNA (mtDNA) 突变是线粒体疾病的主要原因。携带疾病相关mtDNA突变的细胞表现出各种表型异常,例如呼吸减少和乳酸产生增加。来自线粒体疾病患者的诱导性多能干细胞 (iPSC) 系,具有高比例的突变mtDNA,表现出成熟成神经元或心肌细胞的缺陷。在这项研究中,我们发现了一种小分子化合物,我们称之为胰蛋白酶酰胺 (TLAM),可以激活患者来源的线粒体和患者来源的ipsc成纤维细胞产生的半胱氨酸中的线粒体呼吸。我们发现TLAM抑制phosphofructokinase-1 (PFK1),这反过来激活AMPK介导的脂肪酸氧化以促进氧化磷酸化,并将来自糖酵解的碳流重定向到磷酸戊糖途径以增强抗氧化潜力。最后,我们发现TLAM挽救了携带高比例突变mtDNA的iPSCs的神经元分化缺陷,表明PFK1代表了线粒体疾病的潜在治疗靶点。

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