Hypoxic induction of UCP3 in the growth plate: UCP3 suppresses chondrocyte autophagy.
The overall goal of the investigation was to examine the role of uncoupling proteins (UCPs) in regulating late stage events in the chondrocyte maturation pathway. We showed for the first time that epiphyseal chondrocytes expressed UCP3. In hypoxia, UCP3 mediated regulation of the mitochondrial transmembrane potential (DeltaPsi(m)) was dependent on HIF-1alpha. We also showed for the first time that UCP3 regulated the induction of autophagy. Thus, suppression of UCP3 enhanced the expression of the autophagic phenotype, even in serum-replete media. Predictably, the mature autophagic chondrocytes were susceptible to an apoptogen challenge. Susceptibility was probably associated with a lowered expression of the anti-apoptotic proteins Bcl2 and BCL(xL) and a raised baseline expression of cytochrome c in the cytosol. These changes would serve to promote sensitivity to apoptogens. We conclude that in concert with HIF-1alpha, UCP3 regulates the activity of the mitochondrion by modulating the transmembrane potential. In addition, it inhibits induction of the autophagic response. When this occurs, it suppresses sensitivity to agents that promote chondrocyte deletion from the growth plate.
Watanabe
Hitoshi
H
Department of Orthopaedic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Bohensky
Jolene
J
Freeman
Theresa
T
Srinivas
Vickram
V
Shapiro
Irving M
IM
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D045304:Cytochromes c / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D005786:Gene Expression Regulation; D006132:Growth Plate / Q000166:cytology / Q000502:physiology; D000860:Hypoxia; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D000071247:Uncoupling Protein 3
D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D007473:Ion Channels; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3; D045304:Cytochromes c; D019311:Staurosporine; C054207:etomoxir