Enhancement of mitochondrial calcium uptake is cardioprotective against maladaptive hypertrophy by retrograde signaling uptuning Akt
Abstract
Regulation of mitochondrial Ca 2+ uptake is critical in cardiac adaptation to chronic stressors. Abnormalities in Ca 2+ handling, including mitochondrial uptake mechanisms, have been implicated in pathological heart hypertrophy. Enhancing mitochondrial Ca 2+ uniporter (MCU) expression has been suggested to interfere with maladaptive development of heart failure. Here, we addressed whether MCU modulation affects the cardiac response to pressure overload. MCU content was quantified in human and murine hearts at different phases of myocardial hypertrophy. Cardiac function/structure were analyzed after Transverse Aortic Constriction (TAC) in mice undergone viral-assisted overexpression or downregulation of MCU. In vitro and ex vivo assays determined the effect of MCU modulation on mitochondrial Ca 2+ uptake, cellular phenotype and hypertrophic signaling. In human and murine hearts MCU levels increased in the adaptive phase of myocardial hypertrophy and declined in the failing stage. Consistently, modulation of MCU had a cell-autonomous effect in cardiomyocyte/heart adaptation to chronic overload. Indeed, upon TAC MCU-downregulation accelerated development of contractile dysfunction, interstitial fibrosis and heart failure. Conversely, MCU-overexpression prolonged the adaptive phase of hypertrophic response, as, in advanced stages upon TAC, hearts showed preserved contractility, absence of fibrosis and intact vascularization. In vitro and ex vivo analyses indicated that enhancement in mitochondrial Ca 2+ uptake in cardiomyocytes entails “mitochondrion-to-cytoplasm” signals leading to ROS-mediated activation of Akt, which may explain the protective effects towards heart response to TAC. Enhanced mitochondrial Ca 2+ uptake affects the compensatory response to pressure overload via retrograde mitochondrial-Ca 2+ /ROS/Akt signaling, thus uncovering a potentially targetable mechanism against maladaptive myocardial hypertrophy.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (24)
Tania Zaglia
Department of Biomedical Sciences, University of Padova
Antonio Campo
Department of Biomedical Sciences, University of Padova
Nicola Moro
Department of Biomedical Sciences, University of Padova
Vittoria Di Mauro
Department of Biomedical Sciences, University of Padova
Giulia Borile
Department of Biomedical Sciences, University of Padova
Roberta Menabò
Department of Biomedical Sciences, University of Padova
Salvatore Antonucci
Department of Biomedical Sciences, University of Padova
Laura Poli
Department of Biomedical Sciences, University of Padova
Marika Campesan
Department of Biomedical Sciences, University of Padova
Pierluigi Carullo
Istituti di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital
Sara Martinazzi
Division of Cardiac Surgery, University of Verona
Giovanni B. Luciani
Division of Cardiac Surgery, University of Verona
Karin Hammer
Internal Medicine II, University Hospital Regensburg
Paola Pesce
Department of Medicine, University of Padova
Riccardo Bariani
Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova
Giuseppe Faggian
Division of Cardiac Surgery, University of Verona
Lars Maier
Internal Medicine II, University Hospital Regensburg
Laura Ventura
Department of Statistical Sciences, University of Padova
Diego De Stefani
Department of Biomedical Sciences, University of Padova
Cristina Mammucari
Department of Biomedical Sciences, University of Padova
Rosario Rizzuto
Daniele Catalucci
Istituti di Ricovero e Cura a Carattere Scientifico Humanitas Research Hospital
Fabio Di Lisa
Department of Biomedical Sciences, University of Padova
Marco Mongillo
Department of Biomedical Sciences, University of Padova