Mitochondrial pyrimidine nucleotide carrier (PNC1) regulates mitochondrial biogenesis and the invasive phenotype of cancer cells.
The insulin-like growth factor (IGF-I) signalling pathway is essential for metabolism, cell growth and survival. It induces expression of the mitochondrial pyrimidine nucleotide carrier 1 (PNC1) in transformed cells, but the consequences of this for cell phenotype are unknown. Here we show that PNC1 is necessary to maintain mitochondrial function by controlling mitochondrial DNA replication and the ratio of transcription of mitochondrial genes relative to nuclear genes. PNC1 suppression causes reduced oxidative phosphorylation and leakage of reactive oxygen species (ROS), which activates the AMPK-PGC1alpha signalling pathway and promotes mitochondrial biogenesis. Overexpression of PNC1 suppresses mitochondrial biogenesis. Suppression of PNC1 causes a profound ROS-dependent epithelial-mesenchymal transition (EMT), whereas overexpression of PNC1 suppresses both basal EMT and induction of EMT by TGF-beta. Overall, our findings indicate that PNC1 is essential for mitochondria maintenance and suggest that its induction by IGF-I facilitates cell growth whereas protecting cells from an ROS-promoted differentiation programme that arises from mitochondrial dysfunction.
Favre
C
C
Cell Biology Laboratory, Department of Biochemistry, BioSciences Institute, University College Cork, Cork, Ireland.
Zhdanov
A
A
Leahy
M
M
Papkovsky
D
D
O'Connor
R
R
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D019069:Cell Respiration; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000096:biosynthesis; D004847:Epithelial Cells / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D008648:Mesoderm / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D033704:Nucleotide Transport Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
D004272:DNA, Mitochondrial; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D033704:Nucleotide Transport Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C483480:SLC25A33 protein, human; D000255:Adenosine Triphosphate