Mitochondrial dysfunction is induced by the overexpression of UCP4 in 3T3-L1 adipocytes.
Uncoupling proteins (UCPs) belong to a superfamily of mitochondrial transporters that uncouple ATP synthesis from electron transport. We have previously shown that uncoupling protein 4 (UCP4) is differentially expressed in omental adipose tissue in diet-induced obese and normal rats. Overexpression of UCP4 promotes proliferation and inhibits apoptosis and differentiation of preadipocytes. In this work, we further characterized the effect of UCP4 on mitochondrial function in mature 3T3-L1 adipocytes. Transmission electron microscopy (TEM) showed that adipocytes overexpressing UCP4 displayed condensed mitochondria with twisted, condensed, and unclear cristae. Moreover, the loss of the mitochondrial membrane potential and intramitochondrial calcium was found. The adipocytes overexpressing UCP4 also showed decreased mitochondrial copy number (mtDNA) and lower mRNA expression of key factors in mitochondrial biogenesis, including PGC-1alpha and mtTFA. NRF-1 and ERRbeta levels were down-regulated, while NRF-2 levels were upregulated. In addition, UCP4 overexpression impaired mitochondrial fusion and fission, as indicated by decreased mitofusin mfn1, mfn2, and mitofission DRP1. When it came to total adipocytes, the UCP4 overexpressing adipocytes showed higher production reactive oxygen species and diminished levels of intracellular ATP. Furthermore, overexpression of UCP4 brought about impaired insulin sensitivity in adipocytes. UCP4 plays an important role in mitochondrial function and adipocyte insulin resistance. Its function deserves further attention.
Gao
Chun-Lin
CL
Department of Pediatrics, Nanjing Maternal and Child Health Hospital of Nanjing Medical University, Nanjing 210004, P.R. China.
Zhu
Jin-Gai
JG
Zhao
Ya-Ping
YP
Chen
Xiao-Hui
XH
Ji
Chen-Bo
CB
Zhang
Chun-Mei
CM
Zhu
Chun
C
Xia
Zheng-Kun
ZK
Peng
Yu-Zhu
YZ
Guo
Xi-Rong
XR
D041721:3T3-L1 Cells; D000255:Adenosine Triphosphate / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D000071245:Mitochondrial Uncoupling Proteins; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation
D004272:DNA, Mitochondrial; D026901:Membrane Transport Proteins; D000071245:Mitochondrial Uncoupling Proteins; D017382:Reactive Oxygen Species; C547516:Slc25a27 protein, mouse; D000255:Adenosine Triphosphate; D005947:Glucose; D002118:Calcium