A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts
A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts
复制标题
DOI：
10.1073/pnas.0308710100
复制
发表时间：
2004-03-02
影响因子：
11.1
通讯作者：
Larsson, NG
中科院分区：
文献类型：
--
作者：
Hansson, A;Hance, N;Larsson, NG
我们对患有进行性呼吸链缺陷的小鼠心脏进行了全局基因表达分析，发现了疾病早期阶段的代谢转换。本研究的组织特异性线粒体转录因子 A (Tfam) 敲除小鼠表现出进行性心脏表型，线粒体 DNA 耗竭，并伴随呼吸链酶活性严重下降以及线粒体 ATP 生成率下降。这些特征在2周龄后观察到，并逐渐变得更加严重，直到10-12周龄时出现末期。微阵列的整体基因表达分析表明，代谢转换发生在心脏线粒体功能障碍进展的早期。编码脂肪酸氧化中关键酶的大量基因表现出表达减少，而编码糖酵解酶的一些基因表现出表达增加。这些改变与胎儿基因表达程序的激活一致，这是心脏病中一种有据可查的现象。直到疾病发展到晚期才观察到线粒体质量的增加。与我们之前在呼吸链缺陷的骨骼肌中观察到的情况相反，呼吸链缺陷的心肌中线粒体生物发生的增加并没有增加线粒体 ATP 的总体生产率。观察到的代谢转变不太可能有利于呼吸链缺陷心脏的能量稳态，因此可能会加重疾病。因此可以得出结论，线粒体心肌病中至少一些次要基因表达改变不会补偿，而是直接促进心力衰竭进展。
We performed global gene expression analyses in mouse hearts with progressive respiratory chain deficiency and found a metabolic switch at an early disease stage. The tissue-specific mitochondrial transcription factor A (Tfam) knockout mice of this study displayed a progressive heart phenotype with depletion of mtDNA and an accompanying severe decline of respiratory chain enzyme activities along with a decreased mitochondrial ATP production rate. These characteristics were observed after 2 weeks of age and became gradually more severe until the terminal stage occurred at 10-12 weeks of age. Global gene expression analyses with microarrays showed that a metabolic switch occurred early in the progression of cardiac mitochondrial dysfunction. A large number of genes encoding critical enzymes in fatty acid oxidation showed decreased expression whereas several genes encoding glycolytic enzymes showed increased expression. These alterations are consistent with activation of a fetal gene expression program, a well-documented phenomenon in cardiac disease. An increase in mitochondrial mass was not observed until the disease had reached an advanced stage. In contrast to what we have earlier observed in respiratory chain-deficient skeletal muscle, the increased mitochondrial biogenesis in respiratory chain-deficient heart muscle did not increase the overall mitochondrial ATP production rate. The observed switch in metabolism is unlikely to benefit energy homeostasis in the respiratory chain-deficient hearts and therefore likely aggravates the disease. It can thus be concluded that at least some of the secondary gene expression alterations in mitochondrial cardiomyopathy do not compensate but rather directly contribute to heart failure progression.