Developing and testing coarse-grained models of mitochondrial form and function

Abstract

Mitochondria are multifunctional and semiautonomous organelles. They perform respiration in order to produce adenosine triphosphate (ATP), the energy currency which fuels cellular processes. However, the factors that control the rate of mitochondrial respiration and determine cellular mitochondrial content are incompletely understood. Working with the budding yeast Saccharomyces cerevisiae, we show that respiration rate is saturated and that mitochondrial biogenesis is decoupled from the production of other cellular components. Respiration rate is robust to acute perturbations of cellular ATP demand and nutrient supply. Instead, respiration rate is determined by mitochondrial amount due to saturation of the electron transport chain. Mitochondrial accumulation rate is robust to changes in growth conditions, resulting in mitochondrial amount being largely determined by cell division time. A long-standing observation is that in fast-growing cells, respiration rate declines with increasing growth rate and is compensated by an increase in fermentation, even though respiration is more efficient at producing ATP -- a phenomenon known as aerobic glycolysis. Our model of respiration and mitochondrial growth, combined with a kinetic model of glucose uptake, provides a quantitative explanation for aerobic glycolysis in budding yeast.