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Functional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing

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  • Jack Holcombe

    (University of Bristol)

  • Helen Weavers

    (University of Bristol)

Abstract

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.

Suggested Citation

  • Jack Holcombe & Helen Weavers, 2023. "Functional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44098-x
    DOI: 10.1038/s41467-023-44098-x
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    1. Toby Lieber & Swathi P. Jeedigunta & Jonathan M. Palozzi & Ruth Lehmann & Thomas R. Hurd, 2019. "Mitochondrial fragmentation drives selective removal of deleterious mtDNA in the germline," Nature, Nature, vol. 570(7761), pages 380-384, June.
    2. Prasanna Katti & Peter T. Ajayi & Angel Aponte & Christopher K. E. Bleck & Brian Glancy, 2022. "Identification of evolutionarily conserved regulators of muscle mitochondrial network organization," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
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