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.

Inhibition of HSP90 by AUY922 Preferentially Kills Mutant KRAS Colon Cancer Cells by Activating Bim through ER Stress

“…Consistent with the previous finding that ER stress activates Bim transcription through CHOP (19), we found that knockdown of CHOP inhibited AUY922-triggered upregulation of Bim. Indeed, chemical chaperones or overexpression of GRP78, which alleviates ER stress (30), attenuated upregulation of CHOP and Bim by AUY922. On the other hand, siRNA inhibition of GRP78 or XBP-1, two wellestablished prosurvival effectors of the UPR (14,15), enhanced upregulation of Bim and apoptosis caused by AUY922.…”

Maternal obesity reduces oxidative capacity in fetal skeletal muscle of Japanese macaques

“…Additionally, these changes in substrate utilization occurred in parallel with poor functional outcomes including a greater likelihood of cell arrest (unable to form blastocysts) or smaller blastocysts that had a reduced total cell count. Adding to these findings, isolated oocytes from obese mice had increased mitochondria-derived oxidative stress (33), increased intracellular lipids, and reduced mitochondrial membrane potential (34). Together, these data show that substrate metabolism and mitochondrial function are susceptible to the maternal-fetal environment and may lead to persistent changes in the developing fetal tissue; however, to the best of our knowledge, no studies to date have examined the direct effect of maternal obesity on substrate metabolism in fetal or offspring skeletal muscle.…”

When two obese parents are worse than one! Impacts on embryo and fetal development

“…We (87,88) have previously shown that mitochondrial markers (i.e., MitoTracker and JC-1) are altered in oocytes of obese female mice; thus, we examined whether these changes persist in the developing embryo. Maternal HFD alone increased abundance of Mitotracker staining compared with controls (P Ͻ 0.01; Fig.…”

“…mtDNA copy number has been previously shown to be reduced in oocytes of obese female mice and to persist into the blastocysts and fetal tissue (88). To investigate whether this occurred in response to paternal or combined dietinduced obesity we examined fetal livers from all diet crosses.…”

“…For example, maternal obesity is associated with numerous markers of reduced oocyte quality, including impaired maturation (17,35), increased lipid content (86,87), cellular lipotoxicity (87), alterations to mitochondria including ultrastructure (30), membrane potential (32), and mitochondrial DNA (mtDNA) content (32,88), as well as increased reactive oxygen species and depleted glutathione (indicative of oxidative stress) (32,52) and alterations to DNA methylation patterns of key metabolic and imprinting genes in oocytes (29), resulting from reduced DNA methyltransferase levels (28,29). In males, paternal obesity increases sperm oxidative stress and DNA damage (3,38,69,81) and alters sperm microRNA content (23,55), lipid content (20), protein composition (39,51,70,77), and active and repressive chromatin state (68) and global DNA hypomethylation (23).…”