Bischof, Corinne and Mirtschink, Peter and Yuan, Ting and Wu, Meiqian and Zhu, Chaonan and Kaur, Jaskiran and Pham, Minh Duc and Gonzalez-Gonoggia, Suam and Hammer, Marie and Rogg, Eva-Maria and Sharma, Rahul and Bottermann, Katharina and Gercken, Bettina and Hagag, Eman and Berthonneche, Corinne and Sossalla, Samuel and Stehr, Sebastian N. and Maxeiner, Joachim and Duda, Maria Anna and Latreille, Mathieu and Zamboni, Nicola and Martelli, Fabio and Pedrazzini, Thierry and Dimmeler, Stefanie and Krishnan, Jaya (2021) Mitochondrial-cell cycle cross-talk drives endoreplication in heart disease. SCIENCE TRANSLATIONAL MEDICINE, 13 (623): eabi7964. ISSN 1946-6234, 1946-6242
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ACTIVATED PROTEIN-KINASE; CARDIAC-HYPERTROPHY; PRESSURE-OVERLOAD; DE-NOVO; ADENINE-NUCLEOTIDES; ATP-SYNTHASE; DNA-CONTENT; IN-VIVO; MYOCYTES; METABOLISM; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 Sep 2022 13:27 |
| Last Modified: | 27 Sep 2022 13:27 |
| URI: | https://pred.uni-regensburg.de/id/eprint/48104 |
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