title: Suppression of mitochondrial electron transport chain function in the hypoxic human placenta: a role for miRNA-210 and protein synthesis inhibition.
abstract: Fetal growth is critically dependent on energy metabolism in the placenta, which drives active exchange of nutrients. Placental oxygen levels are therefore vital, and chronic hypoxia during pregnancy impairs fetal growth. Here we tested the hypothesis that placental hypoxia alters mitochondrial electron transport chain (ETS) function, and sought to identify underlying mechanisms. We cultured human placental cells under different oxygen concentrations. Mitochondrial respiration was measured, alongside levels of ETS complexes. Additionally, we studied placentas from sea-level and high-altitude pregnancies. After 4 d at 1% O₂ (1.01 KPa), complex I-supported respiration was 57% and 37% lower, in trophoblast-like JEG3 cells and fibroblasts, respectively, compared with controls cultured at 21% O₂ (21.24 KPa); complex IV-supported respiration was 22% and 30% lower. Correspondingly, complex I levels were 45% lower in placentas from high-altitude pregnancies than those from sea-level pregnancies. Expression of HIF-responsive microRNA-210 was increased in hypoxic fibroblasts and high-altitude placentas, whilst expression of its targets, iron-sulfur cluster scaffold (ISCU) and cytochrome c oxidase assembly protein (COX10), decreased. Moreover, protein synthesis inhibition, a feature of the high-altitude placenta, also suppressed ETS complex protein levels. Our results demonstrate that mitochondrial function is altered in hypoxic human placentas, with specific suppression of complexes I and IV compromising energy metabolism and potentially contributing to impaired fetal growth.
authors: Department of Physiology, Development & Neuroscience, and Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom. fc316@cam.ac.uk
authors: Francesca
authors: F
authors: Colleoni
authors: Nisha
authors: N
authors: Padmanabhan
authors: Hong-Wa
authors: HW
authors: Yung
authors: Erica D
authors: ED
authors: Watson
authors: Irene
authors: I
authors: Cetin
authors: Martha C
authors: MC
authors: Tissot van Patot
authors: Graham J
authors: GJ
authors: Burton
authors: Andrew J
authors: AJ
authors: Murray
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D000531:Altitude; D000704:Analysis of Variance; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002460:Cell Line; D045222:Electron Transport Chain Complex Proteins / Q000037:antagonists & inhibitors*; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism* / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D010920:Placenta / Q000503:physiopathology*; D011247:Pregnancy; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D045222:Electron Transport Chain Complex Proteins; C506160:ISCU protein, human; D007506:Iron-Sulfur Proteins; C543800:MIRN210 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C490115:COX10 protein, human; D003576:Electron Transport Complex IV; D019883:Alkyl and Aryl Transferases; D010100:Oxygen
references: Cardiovasc Res. 2006 Dec 1;72(3):430-7
references: 17034771
references: Pediatr Res. 2001 Apr;49(4):490-4
references: 11264431
references: Nat Protoc. 2008;3(6):965-76
references: 18536644
references: N Engl J Med. 2009 Jan 8;360(2):140-9
references: 19129527
references: Placenta. 1998 Nov;19(8):581-6
references: 9859861
references: Pediatr Res. 2003 Jul;54(1):20-5
references: 12700368
references: Birth Defects Res A Clin Mol Teratol. 2011 Aug;91(8):737-43
references: 21425434
references: Am J Pathol. 2011 Aug;179(2):590-602
references: 21801864
references: FEBS Lett. 1994 May 23;345(1):50-4
references: 8194600
references: FASEB J. 2012 May;26(5):1970-81
references: 22267338
references: Genome Med. 2009 Dec 18;1(12):117
references: 20090895
references: Thorax. 2011 Feb;66(2):121-7
references: 21097816
references: High Alt Med Biol. 2003 Summer;4(2):141-56
references: 12855048
references: Am J Obstet Gynecol. 2009 Jun;200(6):661.e1-7
references: 19285651
references: Placenta. 2008 Aug;29(8):680-90
references: 18653232
references: FASEB J. 2012 Apr;26(4):1431-41
references: 22186874
references: Am J Pathol. 2000 Jan;156(1):321-31
references: 10623681
references: Placenta. 2012 Oct;33(10):816-23
references: 22840297
references: Curr Opin Clin Nutr Metab Care. 2007 Nov;10(6):704-11
references: 18089951
references: Hypertension. 2008 Aug;52(2):387-93
references: 18591459
references: Cell Metab. 2009 Oct;10(4):273-84
references: 19808020
references: Placenta. 2012 Nov;33 Suppl 2:e16-22
references: 22742726
references: Oncogene. 2010 Jul 29;29(30):4362-8
references: 20498629
references: Mol Cell Biol. 2007 Mar;27(5):1859-67
references: 17194750
references: Cell Death Differ. 2011 Mar;18(3):465-78
references: 20885442
references: Endocrinology. 1994 Sep;135(3):1135-45
references: 8070357
references: Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7631-6
references: 9636201
references: PLoS One. 2010 Jan 01;5(1):e8551
references: 20049329
references: Am J Obstet Gynecol. 1999 May;180(5):1161-8
references: 10329872
references: Cell Cycle. 2010 Mar 15;9(6):1072-83
references: 20237418
references: Placenta. 2011 Jan;32(1):33-43
references: 21075446
references: Cell Metab. 2006 Mar;3(3):187-97
references: 16517406
references: Biochem J. 1980 Nov 1;191(2):421-7
references: 6263247
references: Cell Metab. 2006 Mar;3(3):150-1
references: 16517402
references: Science. 2005 Jun 10;308(5728):1592-4
references: 15947178
references: Am J Physiol Regul Integr Comp Physiol. 2010 Jan;298(1):R166-72
references: 19864339
references: Cell. 2009 Jan 23;136(2):215-33
references: 19167326
references: Exp Physiol. 2006 Sep;91(5):807-19
references: 16857720
references: Am J Physiol Cell Physiol. 2011 Mar;300(3):C385-93
references: 21123733
references: Science. 1986 Jan 17;231(4735):234-41
references: 2417316
references: J Biol Chem. 1997 May 2;272(18):12236-43
references: 9115299
references: Placenta. 2012 Feb;33(2):122-3
references: 22154690
references: Int J Dev Biol. 2010;54(2-3):409-19
references: 19924633
references: J Physiol. 2009 Feb 1;587(3):693-708
references: 19074967
references: Cell Death Differ. 2008 Apr;15(4):667-71
references: 18219318
references: Pregnancy Hypertens. 2011 Jan;1(1-2):72-8
references: 22242213
references: Taiwan J Obstet Gynecol. 2006 Sep;45(3):189-200
references: 17175463
references: Cancer Biol Ther. 2008 Feb;7(2):255-64
references: 18059191
references: J Anat. 2009 Jul;215(1):27-35
references: 19175804
references: Am J Pathol. 2007 Oct;171(4):1168-79
references: 17823277