Nuclear recruitment of neuronal nitric-oxide synthase by α-syntrophin is crucial for the induction of mitochondrial biogenesis.
Neuronal nitric-oxide synthase (nNOS) has various splicing variants and different subcellular localizations. nNOS can be found also in the nucleus; however, its exact role in this compartment is still not completely defined. In this report, we demonstrate that the PDZ domain allows the recruitment of nNOS to nuclei, thus favoring local NO production, nuclear protein S-nitrosylation, and induction of mitochondrial biogenesis. In particular, overexpression of PDZ-containing nNOS (nNOSα) increases S-nitrosylated CREB with consequent augmented binding on cAMP response element consensus sequence on peroxisome proliferator-activated receptor γ co-activator (PGC)-1α promoter. The resulting PGC-1α induction is accompanied by the expression of mitochondrial genes (e.g., TFAM, MtCO1) and increased mitochondrial mass. Importantly, full active nNOS lacking PDZ domain (nNOSβ) does not localize in nuclei and fails in inducing the expression of PGC-1α. Moreover, we substantiate that the mitochondrial biogenesis normally accompanying myogenesis is associated with nuclear translocation of nNOS. We demonstrate that α-Syntrophin, which resides in nuclei of myocytes, functions as the upstream mediator of nuclear nNOS translocation and nNOS-dependent mitochondrial biogenesis. Overall, our results indicate that altered nNOS splicing and nuclear localization could be contributing factors in human muscular diseases associated with mitochondrial impairment.
From the Department of Biology, University of Rome "Tor Vergata," 00133 Rome, Italy and.
Katia
K
Aquilano
Sara
S
Baldelli
Maria R
MR
Ciriolo
D021581:Active Transport, Cell Nucleus / Q000235:genetics; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D006367:HeLa Cells; D006609:High Mobility Group Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009135:Muscular Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C499631:TFAM protein, human; C081930:Tfam protein, mouse; D014157:Transcription Factors; C091825:syntrophin alpha1; C496320:NOS1 protein, human; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse
Mitochondria; Myogenesis; Nitric-oxide Synthase; S-Nitrosylation; Scaffold Proteins