School of Biochemistry, Biomedical Sciences, University of Bristol, Bristol, BS8 1TD, UK.
Nat Commun. 2023 Dec 18;14(1):8405. doi: 10.1038/s41467-023-44098-x.
Precise coupling between cellular physiology and metabolism is emerging as a vital relationship underpinning tissue health and longevity. Nevertheless, functional-metabolic coupling within heterogenous microenvironments in vivo remains poorly understood due to tissue complexity and metabolic plasticity. Here, we establish the Drosophila renal system as a paradigm for linking mechanistic analysis of metabolism, at single-cell resolution, to organ-wide physiology. Kidneys are amongst the most energetically-demanding organs, yet exactly how individual cell types fine-tune metabolism to meet their diverse, unique physiologies over the life-course remains unclear. Integrating live-imaging of metabolite and organelle dynamics with spatio-temporal genetic perturbation within intact functional tissue, we uncover distinct cellular metabolic signatures essential to support renal physiology and healthy ageing. Cell type-specific programming of glucose handling, PPP-mediated glutathione regeneration and FA β-oxidation via dynamic lipid-peroxisomal networks, downstream of differential ERR receptor activity, precisely match cellular energetic demands whilst limiting damage and premature senescence; however, their dramatic dysregulation may underlie age-related renal dysfunction.
细胞生理学和代谢之间的精确偶联正在成为支持组织健康和长寿的重要关系。然而，由于组织复杂性和代谢可塑性，体内异质微环境中的功能代谢偶联仍然知之甚少。在这里，我们建立了果蝇肾脏系统作为一个范例，将代谢的机制分析，以单细胞分辨率，与器官范围的生理学联系起来。肾脏是能量需求最高的器官之一，但确切地说，单个细胞类型如何微调代谢以满足其在整个生命周期中的不同独特生理学，目前尚不清楚。我们将代谢物和细胞器动态的实时成像与完整功能组织内的时空遗传干扰相结合，揭示了支持肾脏生理学和健康衰老所必需的独特细胞代谢特征。通过差异 ERR 受体活性下游的动态脂质过氧化物酶体网络，对葡萄糖处理、PPP 介导的谷胱甘肽再生和 FA β-氧化进行细胞类型特异性编程，精确匹配细胞能量需求，同时限制损伤和过早衰老；然而，它们的剧烈失调可能是与年龄相关的肾功能障碍的基础。
