Mitochondrial fission is required for cardiomyocyte hypertrophy mediated by a Ca2+-calcineurin signaling pathway.
Cardiomyocyte hypertrophy has been associated with diminished mitochondrial metabolism. Mitochondria are crucial organelles for the production of ATP, and their morphology and function are regulated by the dynamic processes of fusion and fission. The relationship between mitochondrial dynamics and cardiomyocyte hypertrophy is still poorly understood. Here, we show that treatment of cultured neonatal rat cardiomyocytes with the hypertrophic agonist norepinephrine promotes mitochondrial fission (characterized by a decrease in mitochondrial mean volume and an increase in the relative number of mitochondria per cell) and a decrease in mitochondrial function. We demonstrate that norepinephrine acts through α1-adrenergic receptors to increase cytoplasmic Ca(2+), activating calcineurin and promoting migration of the fission protein Drp1 (encoded by Dnml1) to mitochondria. Dominant-negative Drp1 (K38A) not only prevented mitochondrial fission, it also blocked hypertrophic growth of cardiomyocytes in response to norepinephrine. Remarkably, an antisense adenovirus against the fusion protein Mfn2 (AsMfn2) was sufficient to increase mitochondrial fission and stimulate a hypertrophic response without agonist treatment. Collectively, these results demonstrate the importance of mitochondrial dynamics in the development of cardiomyocyte hypertrophy and metabolic remodeling.
Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago 8380492, Chile Centro Estudios Moleculares de la Celula, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Universidad de Chile, Santiago 8380492, Chile.
Christian
C
Pennanen
Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago 8380492, Chile Centro Estudios Moleculares de la Celula, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Universidad de Chile, Santiago 8380492, Chile Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.
Valentina
V
Parra
Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago 8380492, Chile Centro Estudios Moleculares de la Celula, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Universidad de Chile, Santiago 8380492, Chile.
Camila
C
López-Crisosto
Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago 8380492, Chile Centro Estudios Moleculares de la Celula, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Universidad de Chile, Santiago 8380492, Chile.
Pablo E
PE
Morales
Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago 8380492, Chile Centro Estudios Moleculares de la Celula, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Universidad de Chile, Santiago 8380492, Chile.
Andrea
A
Del Campo
Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago 8380492, Chile Centro Estudios Moleculares de la Celula, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Universidad de Chile, Santiago 8380492, Chile.
Tomás
T
Gutierrez
Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago 8380492, Chile Centro Estudios Moleculares de la Celula, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Universidad de Chile, Santiago 8380492, Chile.
Pablo
P
Rivera-Mejías
Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago 8380492, Chile Centro Estudios Moleculares de la Celula, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Universidad de Chile, Santiago 8380492, Chile.
Jovan
J
Kuzmicic
Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago 8380492, Chile Centro Estudios Moleculares de la Celula, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Universidad de Chile, Santiago 8380492, Chile.
Mario
M
Chiong
Institute for Research in Biomedicine (IRB), 08028 Barcelona, Spain Departamento de Bioquímica í Biología molecular, Facultat de Biología, Universitat de Barcelona, Barcelona, Spain CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Spain.
Antonio
A
Zorzano
Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, TX 75235, USA Beverly.Rothermel@UTSouthwestern.edu slavander@uchile.cl.
Beverly A
BA
Rothermel
Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago 8380492, Chile Centro Estudios Moleculares de la Celula, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Universidad de Chile, Santiago 8380492, Chile Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, TX 75235, USA Beverly.Rothermel@UTSouthwestern.edu slavander@uchile.cl.
Sergio
S
Lavandero
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D006332:Cardiomegaly / Q000378:metabolism; D002478:Cells, Cultured; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D020558:GTP Phosphohydrolases; D006984:Hypertrophy / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008929:Mitochondria, Heart / Q000502:physiology*; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D021381:Protein Transport; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism
D000316:Adrenergic alpha-Agonists; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018340:Receptors, Adrenergic, alpha-1; D019703:Calcineurin; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat; C519851:Dnm1l protein, rat; D034281:Dynamins; D002118:Calcium; D009638:Norepinephrine
Calcineurin; Cardiac hypertrophy; Drp1; Metabolism; Mitochondrial fission; Norepinephrine