From hot to cold: dissecting lipidome adaptation in Mycoplasma mycoides and the Minimal Cell JCVI-Syn3B

Cell membranes insulate and mediate interactions between life and its environment, with lipids determining their properties and functions. However, the intricacies of how cells adjust their lipidome compositions to tune membrane properties remain relatively undefined. The complexity of most model organisms has made it challenging to characterize lipidomic adaptation. An ideal model system would be a relatively simple organism with a single membrane that can adapt to environmental changes, particularly temperature, which is known to affect membrane properties. To this end, we used quantitative shotgun lipidomics to analyze temperature adaptation in Mycoplasma mycoides and its minimal synthetic counterpart, JCVI-Syn3B. Comparing with lipidomes from eukaryotes and bacteria, we observed a universal logarithmic distribution of lipid abundances. Additionally, the extent of lipid remodeling needed for temperature adaptation appears relatively constrained, irrespective of lipidomic or organismal complexity. Through lipid features analysis, we demonstrate head group-specific acyl chain remodeling as characteristic of temperature-induced lipidome adaptation and its deficiency in Syn3B is associated with impaired homeoviscous adaptation. Temporal analysis uncovers a two-stage cold adaptation process: swift cholesterol and cardiolipin shifts followed by gradual acyl chain modifications. This work provides an in-depth analysis of lipidome adaptation in minimal cells, laying a foundation to probe the fundamental design principles of living membranes.细胞膜可发挥绝缘作用，并介导生命与外界环境的相互作用，脂质则决定了细胞膜的固有属性与功能。然而，细胞如何调整其脂质组（lipidome）组成以调控细胞膜特性的复杂机制，目前仍未得到充分阐明。多数经典模式生物的系统复杂性，使得脂质组适应性的表征工作面临诸多挑战。理想的模式系统应具备结构相对简单、仅含单层细胞膜且可随环境变化（尤其是已知会影响细胞膜特性的温度）发生适应性调整的特征。为此，本研究采用定量鸟枪法脂质组学（quantitative shotgun lipidomics）技术，对蕈状支原体（Mycoplasma mycoides）及其最小化合成对应株JCVI-Syn3B的温度适应性展开分析。相较于真核生物与细菌的脂质组，我们观察到脂质丰度普遍呈现对数分布特征。此外，无论脂质组复杂度或是生物体整体复杂度如何，温度适应性所需的脂质重塑程度均相对受限。通过对脂质特征的分析，我们证实：以头部基团特异性酰基链重塑为核心的脂质组适应性变化，是温度诱导的脂质组适应的典型特征；而Syn3B中该过程的缺失，与其膜脂恒温适应性（homeoviscous adaptation）受损密切相关。时序分析揭示了两阶段的低温适应过程：首先是胆固醇与心磷脂的快速丰度变化，随后为酰基链的逐步修饰。本研究对最小化细胞的脂质组适应性展开了深入剖析，为探索活细胞膜的核心设计原则奠定了研究基础。