A muscle-specific p38 MAPK/Mef2/MnSOD pathway regulates stress, motor function, and life span in Drosophila.
Molecular mechanisms that concordantly regulate stress, life span, and aging remain incompletely understood. Here, we demonstrate that in Drosophila, a p38 MAP kinase (p38K)/Mef2/MnSOD pathway is a coregulator of stress and life span. Hence, overexpression of p38K extends life span in a MnSOD-dependent manner, whereas inhibition of p38K causes early lethality and precipitates age-related motor dysfunction and stress sensitivity, that is rescued through muscle-restricted (but not neuronal) add-back of p38K. Additionally, mutations in p38K are associated with increased protein carbonylation and Nrf2-dependent transcription, while adversely affecting metabolic response to hypoxia. Mechanistically, p38K modulates expression of the mitochondrial MnSOD enzyme through the transcription factor Mef2, and predictably, perturbations in MnSOD modify p38K-dependent phenotypes. Thus, our results uncover a muscle-restricted p38K-Mef2-MnSOD signaling module that influences life span and stress, distinct from the insulin/JNK/FOXO pathway. We propose that potentiating p38K might be instrumental in restoring the mitochondrial detoxification machinery and combating stress-induced aging.
Cell Biology Department, Emory University School of Medicine, Whitehead Building, Room No. 435, Atlanta, GA 30322, USA.
Alysia
A
Vrailas-Mortimer
Tania
T
del Rivero
Subhas
S
Mukherjee
Sanjay
S
Nag
Alexandros
A
Gaitanidis
Dimitris
D
Kadas
Christos
C
Consoulas
Atanu
A
Duttaroy
Subhabrata
S
Sanyal
D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D048031:JNK Mitogen-Activated Protein Kinases; D008136:Longevity; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009046:Motor Neurons / Q000473:pathology*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D018006:Myogenic Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D050050:Protein Carbonylation; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism
D029721:Drosophila Proteins; C499409:Mef2 protein, Drosophila; D018006:Myogenic Regulatory Factors; D016877:Oxidants; D012333:RNA, Messenger; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases