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

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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.