The E3 ligase Mule protects the heart against oxidative stress and mitochondrial dysfunction through Myc-dependent inactivation of Pgc-1α and Pink1.
Cardiac homeostasis requires proper control of protein turnover. Protein degradation is principally controlled by the Ubiquitin-Proteasome System. Mule is an E3 ubiquitin ligase that regulates cellular growth, DNA repair and apoptosis to maintain normal tissue architecture. However, Mule's function in the heart has yet to be described. In a screen, we found reduced Mule expression in left ventricular samples from end-stage heart failure patients. Consequently, we generated conditional cardiac-specific Mule knockout (Mulefl/fl(y);mcm) mice. Mule ablation in adult Mulefl/fl(y);mcm mice prevented myocardial c-Myc polyubiquitination, leading to c-Myc accumulation and subsequent reduced expression of Pgc-1α, Pink1, and mitochondrial complex proteins. Furthermore, these mice developed spontaneous cardiac hypertrophy, left ventricular dysfunction, and early mortality. Co-deletion of Mule and c-Myc rescued this phenotype. Our data supports an indispensable role for Mule in cardiac homeostasis through the regulation of mitochondrial function via maintenance of Pgc-1α and Pink1 expression and persistent negative regulation of c-Myc.
Toronto General Research Institute, Toronto, 100 College St., M5G 1L7, Ontario Canada.
Keith
K
Dadson
Toronto General Research Institute, Toronto, 100 College St., M5G 1L7, Ontario Canada.
Ludger
L
Hauck
Campbell Family Cancer Research Institute, Princess Margaret Hospital, Toronto, Ontario, Canada.
Zhenyue
Z
Hao
Toronto General Research Institute, Toronto, 100 College St., M5G 1L7, Ontario Canada.
Daniela
D
Grothe
Division of Cardiovascular Surgery, UHN, Toronto, ON, M5G 2C4, Canada.
Vivek
V
Rao
Campbell Family Cancer Research Institute, Princess Margaret Hospital, Toronto, Ontario, Canada.
Tak W
TW
Mak
Toronto General Research Institute, Toronto, 100 College St., M5G 1L7, Ontario Canada.|Division of Cardiology, University Health Network (UHN), Toronto, Ontario, Canada.|Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada.|Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, M5G 1A8, Ontario Canada.
Filio
F
Billia
D000818:Animals; D017209:Apoptosis; D006332:Cardiomegaly / Q000150:complications / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D004734:Energy Metabolism; D005355:Fibrosis; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006333:Heart Failure / Q000150:complications / Q000473:pathology; D006801:Humans; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000473:pathology*; D009928:Organ Specificity; D001678:Organelle Biogenesis; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D055550:Protein Stability; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011494:Protein Kinases; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C502830:HUWE1 protein, human; C502831:Huwe1 protein, mouse