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Bischof 2021 Sci Transl Med

From Bioblast
Publications in the MiPMap
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 (2021) Mitochondrial-cell cycle cross-talk drives endoreplication in heart disease. Sci Transl Med 13:eabi7964.

» PMID: 34878823 Open Access

Bischof Corinne, Mirtschink Peter, Yuan Ting, Wu Meiqian, Zhu Chaonan, Kaur Jaskiran, Pham Minh Duc, Gonzalez-Gonoggia Suam, Hammer Marie, Rogg Eva-Maria, Sharma Rahul, Bottermann Katharina, Gercken Bettina, Hagag Eman, Berthonneche Corinne, Sossalla Samuel, Stehr Sebastian N, Maxeiner Joachim, Duda Maria Anna, Latreille Mathieu, Zamboni Nicola, Martelli Fabio, Pedrazzini Thierry, Dimmeler Stefanie, Krishnan Jaya (2021) Sci Transl Med

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 pro-gression in the failing myocardium.

Bioblast editor: Plangger M

Labels: MiParea: Respiration  Pathology: Cardiovascular 

Coupling state: LEAK, OXPHOS, ET  Pathway:HRR: Oxygraph-2k