title: Mitochondrial dysfunction in oocytes of obese mothers: transmission to offspring and reversal by pharmacological endoplasmic reticulum stress inhibitors.
abstract: Over-nutrition in females causes altered fetal growth during pregnancy and permanently programs the metabolism of offspring; however, the temporal and mechanistic origins of these changes, and whether they are reversible, are unknown. We now show that, in obese female mice, cumulus-oocyte complexes exhibit endoplasmic reticulum (ER) stress, high levels of intracellular lipid, spindle abnormalities and reduced PTX3 extracellular matrix protein production. Ovulated oocytes from obese mice contain normal levels of mitochondrial (mt) DNA but have reduced mitochondrial membrane potential and high levels of autophagy compared with oocytes from lean mice. After in vitro fertilization, the oocytes of obese female mice demonstrate reduced developmental potential and form blastocysts with reduced levels of mtDNA. Blastocysts transferred to normal weight surrogates that were then analyzed at E14.5 showed that oocytes from obese mice gave rise to fetuses that were heavier than controls and had reduced liver and kidney mtDNA content per cell, indicating that maternal obesity before conception had altered the transmission of mitochondria to offspring. Treatment of the obese females with the ER stress inhibitor salubrinal or the chaperone inducer BGP-15 before ovulation increased the amount of the mitochondrial replication factors TFAM and DRP1, and mtDNA content in oocytes. Salubrinal and BGP-15 also completely restored oocyte quality, embryo development and the mtDNA content of fetal tissue to levels equivalent to those derived from lean mice. These results demonstrate that obesity before conception imparts a legacy of mitochondrial loss in offspring that is caused by ER stress and is reversible during the final stages of oocyte development and maturation.
authors: School of Paediatrics and Reproductive Health, Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5005, Australia.
authors: Linda L
authors: LL
authors: Wu
authors: School of Paediatrics and Reproductive Health, Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5005, Australia.
authors: Darryl L
authors: DL
authors: Russell
authors: School of Paediatrics and Reproductive Health, Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5005, Australia.
authors: Siew L
authors: SL
authors: Wong
authors: School of Paediatrics and Reproductive Health, Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5005, Australia.
authors: Miaoxin
authors: M
authors: Chen
authors: Centre for Genetic Diseases, MIMR-PHI Institute of Medical Research, and Department of Molecular and Translational Science, Monash University, Clayton, VIC, 3168, Australia.
authors: Te-Sha
authors: TS
authors: Tsai
authors: Centre for Genetic Diseases, MIMR-PHI Institute of Medical Research, and Department of Molecular and Translational Science, Monash University, Clayton, VIC, 3168, Australia.
authors: Justin C
authors: JC
authors: St John
authors: School of Paediatrics and Reproductive Health, Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5005, Australia.
authors: Robert J
authors: RJ
authors: Norman
authors: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, 3004, Australia.
authors: Mark A
authors: MA
authors: Febbraio
authors: School of Biomedical Sciences, Nursing and Health Sciences, Monash University, Clayton, VIC, 3800, Australia.
authors: John
authors: J
authors: Carroll
authors: School of Paediatrics and Reproductive Health, Robinson Research Institute, The University of Adelaide, Adelaide, SA, 5005, Australia Rebecca.robker@adelaide.edu.au.
authors: Rebecca L
authors: RL
authors: Robker
mesh_terms: D000818:Animals; D002934:Cinnamates / Q000494:pharmacology; D004272:DNA, Mitochondrial / Q000235:genetics; D059865:Endoplasmic Reticulum Stress; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009765:Obesity / Q000235:genetics / Q000503:physiopathology*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D010091:Oximes / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D002934:Cinnamates; D004272:DNA, Mitochondrial; D010091:Oximes; D010880:Piperidines; C496827:salubrinal; D013890:Thiourea; C405586:BGP 15
keywords: BGP-15; ER stress; Mitochondria; Obesity; Ovary; mtDNA