Phosphoenolpyruvate carboxykinase 1-mediated cataplerosis is required to maintain mitochondrial fitness and to avoid kidney disease progression

Article Article scientifique Article Phosphoenolpyruvate carboxykinase 1-mediated cataplerosis is required to maintain mitochondrial fitness and to avoid kidney disease progression eng 2025-07-09 author Dalga Delal Department of cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland; Department of Medicine, Service of Nephrology, Geneva University Hospitals, Geneva, Switzerland. 816613 Département de médecine (DEMED) author Rinaldi Anna Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Department of Biomedicine, University of Basel, Basel, Switzerland. author Fu Xiaorong Center for Human Nutrition and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA. author Chanvillard Lucie School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne 1015, Switzerland. author Huber Aurélie Charlotte Department of Medicine, Service of Nephrology, Geneva University Hospitals, Geneva, Switzerland. 852309 Département de médecine (DEMED) author Faivre Anna 0000-0002-1752-7533 Department of cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland; Department of Medicine, Service of Nephrology, Geneva University Hospitals, Geneva, Switzerland. 801532 author Jaques David Department of Medicine, Service of Nephrology, Geneva University Hospitals, Geneva, Switzerland. 633322 Département de médecine (DEMED) author Berchtold Lena Department of Medicine, Service of Nephrology, Geneva University Hospitals, Geneva, Switzerland. 635029 Département de médecine (DEMED) author Boccard Julien 0000-0001-5913-9566 School of Pharmaceutical Sciences, University of Geneva, Geneva, Switzerland. 507373 Section des sciences pharmaceutiques (FARMA) author Arnoux Grégoire Department of cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland; Division of Clinical Pathology, Department of Diagnostics, Geneva University Hospitals, Geneva, Switzerland. 674746 author Lyon Arnaud Department of Vascular Surgery, University Hospital of Lausanne (CHUV), Lausanne, Switzerland; Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. author Rutkowski Joseph M Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. author Gex Quentin Department of cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland; Department of Medicine, Service of Nephrology, Geneva University Hospitals, Geneva, Switzerland. 701133 Département de médecine (DEMED) author Paolucci Deborah Department of cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland; Department of Medicine, Service of Nephrology, Geneva University Hospitals, Geneva, Switzerland. 785913 Département de médecine (DEMED) author Kreutzfeldt Mario Division of Clinical Pathology, Department of Diagnostics, Geneva University Hospitals, Geneva, Switzerland. 736806 Département de pathologie et immunologie (PATIM) author Cagarelli Thomas Division of Clinical Pathology, Department of Diagnostics, Geneva University Hospitals, Geneva, Switzerland. 759364 author Lutz Lea Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Department of Biomedicine, University of Basel, Basel, Switzerland. author Longchamp Alban Transplant Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. author Moll Solange Division of Clinical Pathology, Department of Diagnostics, Geneva University Hospitals, Geneva, Switzerland. 28349 Département de pathologie et immunologie (PATIM) author Hulo Nicolas Institute of Genetics and Genomics of Geneva, Université de Genève, Genève, Switzerland. 29577 Administration de la section de biologie (BIAD) author Ponte Belen Department of Medicine, Service of Nephrology, Geneva University Hospitals, Geneva, Switzerland. 89158 Département de médecine (DEMED) author Burgess Shawn C Center for Human Nutrition and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA. author Cippà Pietro E Laboratories for Translational Research, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Department of Biomedicine, University of Basel, Basel, Switzerland. author Verissimo Thomas 0000-0001-6854-6315 Department of cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland; Department of Medicine, Service of Nephrology, Geneva University Hospitals, Geneva, Switzerland. 933088 author De Seigneux Matthey Sophie Department of cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland; Department of Medicine, Service of Nephrology, Geneva University Hospitals, Geneva, Switzerland. Electronic address: Sophie.deseigneux@hug.ch. 105798 Département de médecine (DEMED) 10.1016/j.kint.2025.06.018 40645291 0085-2538 https://www.sciencedirect.com/science/article/pii/S0085253825005137 Introduction: Metabolic alterations are recognized as key features of kidney injury, but their causal role in kidney repair remains debatable. Here, we investigate the role of phosphoenolpyruvate carboxykinase 1 (PCK1), an enzyme involved in gluconeogenesis and cataplerosis (removal of tricarboxylic acid (TCA) cycle intermediates from the mitochondrial matrix) in kidney disease progression. Methods: We used mice with kidney tubular cell-specific deletion or overexpression of the PCK1 enzyme, and different models of kidney injury such as ischemia-reperfusion injury or cis-platin-induced nephropathy. Furthermore, we measured metabolites in kidney biopsy tissue from patients with stage 3b/4 chronic kidney disease (CKD). Results: Using flux analysis, we confirm that cataplerosis and the TCA cycle are blocked by PCK1 deficiency. This results in injured mitochondria leading to inflammation, tubular injury and impaired tubular cell repair. Inversely, maintaining PCK1 function in different models of kidney injury preserves kidney structure, improves TCA cycle metabolite clearance and increase ATP production. In kidney biopsies from different patient cohorts, we confirm the correlation between PCK1 loss, mitochondrial injury and a failed tubular cell repair phenotype. Furthermore, in CKD, accumulation of TCA cycle metabolites is consistent with disrupted cataplerosis. Conclusions: Overall, we demonstrate that PCK1 loss in kidney tubular cells leads to decreased respiration and the accumulation of TCA cycle metabolites. Maintenance of cataplerosis is an important factor of tubular physiology and repair, with PCK1 serving as a causal and potential therapeutic target in this process. PCK1 restoration enhances mitochondrial health, limiting progression to inflammation and fibrosis. Cataplerosis Kidney disease Mitochondria PCK1 Dewey 612 Dewey 615 Dewey 616.07 Dewey 616 Dewey 590 Swiss National Science Foundation Role of tubular cells in CKD progression: At the crossroad between mitochondrial function, acid base metabolism and glucose production 204187 CH Projects Swiss National Science Foundation The role of PCK1 in kidney health and disease 214547 CH Careers Swiss National Science Foundation Development of multimodal MRI to assess the quality of a kidney allograft 221874 CH Careers 137 Département de pathologie et immunologie 21F 31 Section des sciences pharmaceutiques 17 56 Département de médecine 221 134 Département de physiologie cellulaire et métabolisme 21C 23 Institut de génétique et de génomique 0DH false 881 Sciences analytiques 897 Insuffisance rénale chronique 941 393 Analyse protéomique et Analyse génomique des maladies rénales 659 https://zenodo.org/records/13737520 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE280120 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE280119 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE280118 Kidney international 5ef69ace-f3f7-460b-9794-88300945f22b Article (Accepted version) Public Article.pdf 10879711 application/pdf CC BY-4.0 5b1720494aba98ebeb3f7fd2f1063989b49e4c8ecde75476d3578ebe8db1701e 41458ed3-7396-41db-ae24-87606688afde Supplemental data Public ScienceDirect_files_28Jul2025_09-26.zip 4001457 application/zip 6cd310d39ecc3644af2ae9f488092bdc4835e759b693e759f7d16b36d477f175 Vignette Public 1-s2.0-S0085253825005137-ga1_lrg.jpg 176790 image/png openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté des sciences / Section des sciences pharmaceutiques Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme Centres et instituts / Institut de génétique et de génomique

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Huber, Aurélie Charlotte