Molecular crowding defines a common origin for the Warburg effect in proliferating cells and the lactate threshold in muscle physiology

Aerobic glycolysis is a seemingly wasteful mode of ATP production that is seen both in rapidly proliferating mammalian cells and highly active contracting muscles, but whether there is a common origin for its presence in these widely different systems is unknown. To study this issue, here we develop a model of human central metabolism that incorporates a solvent capacity constraint of metabolic enzymes and mitochondria, accounting for their occupied volume densities, while assuming glucose and/or fatty acid utilization. The model demonstrates that activation of aerobic glycolysis is favored above a threshold metabolic rate in both rapidly proliferating cells and heavily contracting muscles, because it provides higher ATP yield per volume density than mitochondrial oxidative phosphorylation. In the case of muscle physiology, the model also predicts that before the lactate switch, fatty acid oxidation increases, reaches a maximum, and then decreases to zero with concomitant increase in glucose utilization, in agreement with the empirical evidence. These results are further corroborated by a larger scale model, including biosynthesis of major cell biomass components. The larger scale model also predicts that in proliferating cells the lactate switch is accompanied by activation of glutaminolysis, another distinctive feature of the Warburg effect. In conclusion, intracellular molecular crowding is a fundamental constraint for cell metabolism in both rapidly proliferating- and non-proliferating cells with high metabolic demand. Addition of this constraint to metabolic flux balance models can explain several observations of mammalian cell metabolism under steady state conditions

Shifting baselines for species in chronic decline and assessment of conservation status. Are hazel dormice Muscardinus avellanarius endangered?

•1. Long-term data are beneficial for monitoring the conservation status of species. Assessments of population change over recent periods of fixed duration will, however, be subject to ‘shifting baselines’, where the accepted norm for the population at the start of the period already represents a reduction from historical levels. International Union for Conservation of Nature Red List criteria for categorizing conservation threat rely on assessing declines against quantitative thresholds, generally measured over 10 years, as indications of the likelihood of extinction in the near future. By contrast, legal frameworks such as the European Habitats Directive require states to achieve and sustain ‘Favourable Conservation Status’ for protected species, while domestic conservation legislation can have more diverse objectives and mechanisms, based on local contexts that extend beyond biological or quantitative criteria. •2. We explore the challenges associated with assessing the risk of extinction and the conservation status that arise from the availability of long-term monitoring data for hazel dormice Muscardinus avellanarius in the United Kingdom. •3. Numbers of adult dormice counted in the National Dormouse Monitoring Programme are in ongoing decline, amounting to an overall decline of 78% (95% confidence interval = 72%–84%) over 27 years, 1994–2020. If the observed annual rate of decline of 5.7% (95% CI = 4.7%–6.8%) were to continue unabated, dormouse counts would decline by >90% from 1994 to 2034. Despite this, the species would never be categorized as Endangered, under IUCN criteria, which specify a reduction of >50% within 10 years. •4. While such chronic decline may not indicate imminent risk of extinction, justifying a higher Red List category, it is a demonstration of unfavourable conservation status at a national scale. Prioritization based on demonstration of such chronic declines might direct more effective action towards species conservation at a point when their recovery is more attainable, rather than attempting later to reverse a journey to the brink of extinction when the species is finally ‘Endangered’