IRCCS Policlinico San Donato
Published February 3, 2022 | Version v1
Dataset Restricted

Mitochondrial-cell cycle cross-talk drives endoreplication in heart disease

Authors/Creators

  • 1. MRC Clinical Sciences Centre, Imperial College London, London W12 0NN, UK.
  • 2. Institute of Clinical Chemistry and Laboratory Medicine, Department of Clinical Pathobiochemistry, University Hospital Dresden, Fetscherstasse 74, 01307 Dresden, Germany.
  • 3. Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
  • 4. Genome Biologics, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
  • 5. Institute of Molecular Systems Biology, ETH Zurich, Zurich 8093, Switzerland.
  • 6. Molecular Cardiology Laboratory, IRCCS-Policlinico San Donato, 20097, San Donato Milanese, Milan, Italy.
  • 7. Department of Medicine, University of Lausanne Medical School, CHUV, MP14-220, 1011 Lausanne, Switzerland.
  • 8. DZHK Partner Site RheinMain, Mainz, Germany.
  • 9. Cardio-Pulmonary Institute, Giessen, Germany.

Description

Dataset from Bischof C, Mirtschink P, Yuan T, Wu M, Zhu C, Kaur J, Pham MD, Gonzalez-Gonoggia S, Hammer M, Rogg EM, Sharma R, Bottermann K, Gercken B, Hagag E, Berthonneche C, Sossalla S, Stehr SN, Maxeiner J, Duda MA, Latreille M, Zamboni N, Martelli F, Pedrazzini T, Dimmeler S, Krishnan J. Mitochondrial-cell cycle cross-talk drives endoreplication in heart disease. Sci Transl Med. 2021 Dec 8;13(623):eabi7964. doi: 10.1126/scitranslmed.abi7964. Epub 2021 Dec 8. PMID: 34878823.

Abstract

Endoreplication, duplication of the nuclear genome without cell division, occurs in disease to drive morphologic growth, cell fate, and function. Despite its criticality, the metabolic underpinnings of disease-induced endoreplication and its link to morphologic growth are unknown. Heart disease is characterized by endoreplication preceding cardiac hypertrophy. We identify ATP synthase as a central control node and determinant of cardiac endoreplication and hypertrophy by rechanneling free mitochondrial ADP to methylenetetrahydrofolate dehydrogenase 1 L (MTHFD1L), a mitochondrial localized rate-limiting enzyme of formate and de novo nucleotide biosynthesis. Concomitant activation of the adenosine monophosphate–activated protein kinase (AMPK)–retinoblastoma protein (Rb)-E2F axis co-opts metabolic products of MTHFD1L function to support DNA endoreplication and pathologic growth. Gain- and loss-of-function studies in genetic and surgical mouse heart disease models and correlation in individuals confirm direct coupling of deregulated energetics with endoreplication and pathologic overgrowth. Together, we identify cardiometabolic endoreplication as a hitherto unknown mechanism dictating pathologic growth progression in the failing myocardium.

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