Respiratory chain inactivation links cartilage-mediated growth retardation to mitochondrial diseases
Respiratory chain inactivation links cartilage-mediated growth retardation to mitochondrial diseases
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DOI：
10.1083/jcb.201809056
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发表时间：
2019-06-01
影响因子：
7.8
通讯作者：
Brachvogel, Bent
中科院分区：
文献类型：
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作者：
Holzer, Tatjana;Probst, Kristina;Brachvogel, Bent
在儿童时期，骨骼的生长是由生长板中软骨的短暂扩张驱动的。一般认为，这种缺氧组织中的能量产生主要依赖于无氧糖酵解，而不是线粒体呼吸链（RC）活性。然而，患有线粒体疾病导致RC功能障碍的儿童通常表现为身材矮小，这表明RC活性可能是软骨介导的骨骼生长所必需的。为了阐明线粒体RC在软骨生长和病理学中的作用，我们产生了软骨中RC功能受损的小鼠。这些小鼠在出生前发育正常，但后来的生长发育迟缓。详细的分子分析显示，代谢信号和细胞外基质形成受到干扰，并诱导软骨-骨连接处的细胞死亡，导致软骨发育不良样表型。因此，这些结果表明了从胎儿糖酵解到出生后生长板软骨中RC激活的代谢转换的总体重要性，并解释了为什么RC功能障碍会导致线粒体疾病儿童身材矮小。
In childhood, skeletal growth is driven by transient expansion of cartilage in the growth plate. The common belief is that energy production in this hypoxic tissue mainly relies on anaerobic glycolysis and not on mitochondrial respiratory chain (RC) activity. However, children with mitochondrial diseases causing RC dysfunction often present with short stature, which indicates that RC activity may be essential for cartilage-mediated skeletal growth. To elucidate the role of the mitochondrial RC in cartilage growth and pathology, we generated mice with impaired RC function in cartilage. These mice develop normally until birth, but their later growth is retarded. A detailed molecular analysis revealed that metabolic signaling and extracellular matrix formation is disturbed and induces cell death at the cartilage-bone junction to cause a chondrodysplasia-like phenotype. Hence, the results demonstrate the overall importance of the metabolic switch from fetal glycolysis to postnatal RC activation in growth plate cartilage and explain why RC dysfunction can cause short stature in children with mitochondrial diseases.