线粒体基因突变的持续上升导致疾病的突变

一个先驱科学家的新工作，详细介绍了线粒体功能的细微变化，可能会导致广泛的共同代谢和退行性疾病。线粒体是我们细胞内的微小的能量产生的结构，含有它们自己的基因。

新的研究表明，小的变化在突变体比正常的线粒体DNA在每个细胞内的线粒体DNA上会导致在核DNA在众多基因表达的突变。此外，不同比例的突变线粒体基因，导致核基因表达的改变对应于相同比例的线粒体基因突变与糖尿病和自闭症，脑，心脏和肌肉疾病，或致命的婴儿疾病。

“显示出微妙的变化，在相同的线粒体DNA突变的细胞比例可能会带来一系列的不同的临床表现，这些发现挑战了一个单一的突变会导致一种疾病的传统模式，”该研究的负责人Douglas C。华勒斯博士，在费城儿童医院的线粒体和表观基因医学中心主任。他补充说，“这项研究提供了重要的见解，了解代谢和神经退行性疾病如糖尿病、老年痴呆症的根本原因，帕金森和亨廷顿病，以及人体衰老。”

华勒斯说：“核基因表达的离散变化对线粒体基因突变水平的小的变化是类似于相变导致的冰增加热量的结果。“随着热量的增加，冰突然转向水，并有更多的热量，水突然变成蒸汽。”这里有一个定量的改变（线粒体基因突变的比例越来越大），结果在一个质的变化（在临床症状上的离散变化的核基因表达的坐标变化）。

这项由华勒斯和同事们的研究在网上出现了9月3日国家科学院学报。

Existing in hundreds or thousands of copies outside the nucleus of every cell, mitochondria have their own DNA, distinct from the well-known DNA inside the cell nucleus。 Although mitochondrial DNA (mtDNA) holds far fewer genes than nuclear DNA, mtDNA exchanges signals with nuclear DNA and participates in complicated networks of biochemical reactions essential to life。

Wallace’s current study rests on his investigations into the mysteries of mitochondria for over 40 years。 In 1988, he was the first to demonstrate that mitochondrial DNA mutations can cause human disease。 He has continued to build a body of research into mechanisms by which mutations in mtDNA contribute to both rare and common diseases by disrupting the body’s energy production。In the current study, Wallace’s team investigated the impacts of steadily increasing levels of a pathogenic mutation in one particular base of mitochondrial DNA。

Researchers already knew that if 10 to 30 percent of a person’s mitochondrial DNA has this mutation, a person has diabetes, and sometimes autism。 Individuals with an mtDNA mutation level of 50 to 90 percent have other multisystem diseases, particularly MELAS syndrome, a severe condition which involves brain and muscle impairments。 Above the 90 percent level, patients die in infancy。

In the current study, conducted in cultured human cells, Wallace and colleagues analyzed cells with different levels of this pathogenic mtDNA mutation to determine the effects on the gene expression of the cell。 The researchers measured variations in cellular structure and function, nuclear gene expression, and production of different proteins。

“The mutations in mitochondria impair their ability to produce energy, and mitochondria transmit distress signals to the cell nucleus,” said Wallace。 “But the nucleus can respond in only a limited number of ways。” Those responses may manifest themselves in discrete, profound consequences for patients。

Wallace argues that the medical significance of this research extends beyond the province of the relatively rare disorders typically classified as mitochondrial diseases。 The gene expression profile — the pattern of gene activity seen at the level at which mtDNA mutations trigger brain disorders — parallels the profiles found in Alzheimer, Parkinson and Huntington diseases。 “The findings in this study provide strong support for the concept that common metabolic diseases such as diabetes and obesity, heart and muscle diseases, and neurodegenerative diseases have underpinnings in energy deficiencies from malfunctioning mitochondria,” said Wallace。 “Thus this concept brings together a cluster of diseases previously considered to be separate from one another。”

Significantly, Wallace added that the research also pertains to aging。 Because mitochondrial mutations accumulate as people age, mitochondrial energy production declines, with deleterious effects on the heart, the brain and on interrelated biological systems that sustain health and life。

Next steps in research, says Wallace, include investigations of how different diseases are associated with the sorts of abrupt phase changes his group found in the current cellular study。 Some of the cellular changes, signaling patterns and protein activity levels found in the current research might become useful biomarkers in disease studies and drug development。 “For instance, a preclinical screen for potential drugs that could reverse gene expression profile changes of the mitochondrial DNA mutant cells could reveal new therapies,” he added。

Wallace’s current study reinforces arguments he has presented over the course of his career, that mitochondria play a central, largely under-recognized role in all common human diseases。 He has long argued that a traditional biomedical approach focusing on anatomy and individual organs does not provide the insights generated from a systems biology, bioenergetics-focused approach。

Wallace’s paradigm-shifting hypotheses remain controversial in biomedicine。 This latest study, he says, implies that the complexity of common diseases is rooted in the disconnect between continuous, linear changes in mtDNA mutations and the discontinuous, sudden phase changes in nuclear gene expression that result。 Even as his overall arguments about the role of mitochondria contend for broader acceptance, the current findings may provide useful, versatile tools for understanding and treating disease。

The Simon Foundation and the National Institutes of Health (grants NS21328, NS070298, AG24373, and DK73691) supported this study。 Wallace’s co-authors are from China, Poland, Australia, France and other U。S。 institutions。

“逐步增加线粒体3243a >；G突变异质性导致转录重编程，”国家科学院学报, Early Edition published online Sept。 3, 2014。 

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