The Flux Capacitor: How mitochondria modulate metabolic flux and gene expression

线粒体通常被称为细胞的动力源，因为它们几乎产生了生命所需的所有能量。最近的研究表明，线粒体不仅仅是产生能量：它们几乎整合了细胞的所有新陈代谢输入和输出。这些投入和产出取决于饮食、温度、生长、年龄和身体需求。如果线粒体不能匹配代谢供需，它们就会向细胞核发出应激状态的信号，导致基因活性的变化。这些变化可能会缓解压力，或者如果失败，细胞可能会走向程序性死亡。线粒体可以被视为“通量电容器”。问题是，线粒体特别容易受到机械故障的影响。这是因为进行呼吸的重要蛋白质是由两个不同的基因组编码的，这两个基因组有分化的趋势-线粒体中的基因突变速度几乎是细胞核中基因突变的50倍，而且只从母亲那里遗传，而细胞核中的基因每一代都会通过性别重组。这些根本性的遗传差异可能会导致错配，从而影响线粒体的性能--通量电容器本身就会出现故障，从而影响细胞的输入和输出，以及细胞的应力状态。线粒体或核基因编码呼吸相关蛋白质的突变可能会导致灾难性的疾病，而更微妙的遗传差异会导致糖尿病、癌症、神经退化和衰老等常见疾病。但线粒体和核基因之间的不匹配在整个生命过程中对健康的影响程度尚不确定，因为每个细胞中都有数百个线粒体，它们的表现可能有很大差异。动物模型表明，“有丝分裂核不匹配”确实会影响健康，例如导致男性不育和寿命延长。即使对健康的影响太微妙而不被注意到，有丝分裂核错配也会改变数千个基因的活性。由于这些错配是每一代人都会产生的，它们很可能会对健康产生重大影响。然而，直到最近，这几乎是不可能得到证实的。我们的研究计划将分析有丝分裂核错配如何影响线粒体的输入和输出，以及这些变化如何影响基因活动和健康。我们将使用一种模式生物，果蝇，在这种生物中，线粒体基因被故意与核基因组错配。这些果蝇的健康状况是已知的，比如雄性不育，但它们有缺陷的线粒体是如何导致这些缺陷的尚不清楚；出于同样的原因，可能改善它们健康的治疗方法也是未知的。我们将使用尖端的实验方法来解决这些问题。具体地说，我们将实时测量线粒体的性能，以确定有丝分裂错配如何在男性和女性的生命过程中改变不同组织的功能，以及线粒体的性能如何通过饮食治疗而改变。我们将生成代谢物水平的全球概况，使我们能够将线粒体功能与每个组织的‘代谢概况’联系起来。最后，我们将使用下一代测序来测量男性和女性在每个治疗过程中每个组织中基因活性的变化。我们将利用这些信息建立一套数学模型，将线粒体功能的变化映射到代谢流量、基因活动和健康的变化，使我们能够总结出对人类和动物健康有价值的结论。我们的初步研究表明，我们确实可以测量与男性不育有关的线粒体性能的实时变化。抗氧化剂治疗根据有丝分裂核不匹配而产生显著不同的结果，在一个案例中，提高了男性的生育力，但导致雌性果蝇的高死亡率(90%)。因此，我们预计我们的发现将对终身健康产生重要影响。

Mitochondria are often called the powerhouses of the cell as they produce nearly all the energy needed for living. Recent research shows that mitochondria do much more than generate energy: they integrate virtually all metabolic inputs and outputs of cells. These inputs and outputs depend on diet, temperature, growth, age and physical demands. If mitochondria cannot match metabolic supply to demand, they signal a stress state to the nucleus resulting in changes in the activity of genes. These changes might ameliorate the stress, or if that fails, tip the cell towards programmed death. Mitochondria can be seen as 'flux capacitors'.The problem is that mitochondria are uniquely vulnerable to mechanical faults. This is because the vital proteins that carry out respiration are encoded by two different genomes that have a tendency to diverge - genes in the mitochondria mutate nearly 50 times faster than those in the nucleus, and are inherited from the mother only, whereas genes in the nucleus are recombined by sex every generation. These radical differences in inheritance can result in mismatches that affect the performance of mitochondria - the flux capacitor itself becomes faulty, which impacts on both the inputs and outputs of the cell, and its stress state. Mutations in either the mitochondrial or nuclear genes encoding the proteins involved in respiration can cause catastrophic diseases, and more subtle genetic differences contribute to common conditions such as diabetes, cancer, neurodegeneration and ageing. But the extent to which mismatches between mitochondrial and nuclear genes affect health through the lifecourse is uncertain, as there are hundreds of mitochondria in every cell, and their performance can differ substantially. Animal models show that 'mitonuclear mismatches' really do affect health, for example causing male infertility and altered lifespan. Even when the health effects are too subtle to notice, mitonuclear mismatches can alter the activity of thousands of genes. Because these mismatches are produced every generation, they most likely have substantial health impacts. Until recently, though, this has been nearly impossible to verify. Our programme of research will analyse how mitonuclear mismatches affect the inputs and outputs of mitochondria, and how these changes impact on gene activity and health. We will use a model organism, the fruitfly Drosophila, in which mitochondrial genes have been deliberately mismatched to the nuclear genome. These flies have known health outcomes such as male infertility, but how their faulty mitochondria cause these defects is unknown; treatments that might improve their health are unknown for the same reasons. We will address these questions using cutting-edge experimental methods. Specifically, we will measure mitochondrial performance in real time to establish how mitonuclear mismatches alter the function of different tissues over the lifecourse of males and females, and how mitochondrial performance is altered by dietary treatments. We will generate global profiles of metabolite levels, allowing us to relate mitochondrial function to the 'metabolomic profile' of each tissue. Finally, we will use Next Generation Sequencing to measure changes in gene activity in each tissue, with each treatment, in males and females. We will use this information to build a set of mathematical models that map changes in mitochondrial function to shifts in metabolic flux, gene activity and health, allowing us to generalise our conclusions to be valuable for human and animal health.Our pilot studies show that we can indeed measure real-time changes in mitochondrial performance linked with male infertility. Antioxidant treatments have remarkably different outcomes depending on mitonuclear mismatches, in one case improving male fertility yet causing high (90%) mortality in female flies. We therefore anticipate our findings will have important implications for lifelong health.