期刊
HUMAN MOLECULAR GENETICS
卷 30, 期 21, 页码 2012-2026出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddab168
关键词
-
资金
- Swedish Cancer Society [20 0681 ReVS 01 H, 0730 PjVSF 01]
- Swedish Research Council [2017-01330, 2018-06156]
The extended survival of DGUOK deficiency in mice is attributed to the activation of serine synthesis, folate cycle, mitochondrial citric acid cycle, urea cycle, and the coordination of two pyruvate kinase genes PKLR and PKM. These molecular pathways play crucial roles in supporting long-term survival despite mitochondrial dysfunction.
Deoxyguanosine kinase (DGUOK) deficiency causes mtDNA depletion and mitochondrial dysfunction. We reported long survival of DGUOK knockout (Dguok(-/-)) mice despite low (<5%) mtDNA content in liver tissue. However, the molecular mechanisms enabling the extended survival remain unknown. Using transcriptomics, proteomics and metabolomics followed by in vitro assays, we aimed to identify the molecular pathways involved in the extended survival of the Dguok(-/-) mice. At the early stage, the serine synthesis and folate cycle were activated but declined later. Increased activity of the mitochondrial citric acid cycle (TCA cycle) and the urea cycle and degradation of branched chain amino acids were hallmarks of the extended lifespan in DGUOK deficiency. Furthermore, the increased synthesis of TCA cycle intermediates was supported by coordination of two pyruvate kinase genes, PKLR and PKM, indicating a central coordinating role of pyruvate kinases to support the long-term survival in mitochondrial dysfunction.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据