Metabolic heat flow from the minimal cell JCVI-Syn3B reveals the lipidome-dependence of growth and metabolism

The cell membrane facilitates interactions with the environment and serves as an organizational platform for coordinating cellular processes, with lipids playing a central role in determining membrane property and function. Yet, how lipidome composition influences cellular fitness remains poorly defined. Recent approaches to chemically tune and minimize the lipidomes of genomically minimized bacterial organisms such as JCVI-Syn3A/B offer a streamlined system to explore why cells need such diverse lipid chemistries. In this study, we use isothermal microcalorimetry to assess how changes in lipid composition affect heat dissipated by JCVI-Syn3B cells, a parameter reflecting both growth and metabolic efficiency. By transposing the Monod equation into a calorimetric equation and extending it to the full life times of batch cultures, we introduce a new approach to quantify the metabolic efficiency of JCVI-Syn3B. Remarkably, our results demonstrate that tuning lipidome composition results in considerable variations of energy dissipation at the expense of biomass production. As a consequence, the volume of these minimal cells becomes inversely coupled to the lipidome-dependent entropic cost of cell division. The corresponding change in heat flow per cell mass gives rise to a complex but systematic dependence of growth rates on lipid composition. Interestingly, the maximal rate correlates with maximal lipid diversity, suggesting that the ability to tune local cell membrane charge and curvature through lipid structural diversity is crucial for divisome function. Our observations highlight the critical role of lipidome composition in cell metabolism and growth, and provide a new tool for interrogating the relationship between membrane composition and cell fitness.