PMID- 33428278 OWN - NLM STAT- MEDLINE DCOM- 20210624 LR - 20211214 IS - 1530-6860 (Electronic) IS - 0892-6638 (Linking) VI - 35 IP - 2 DP - 2021 Feb TI - Nanoparticle-encapsulated antioxidant improves placental mitochondrial function in a sexually dimorphic manner in a rat model of prenatal hypoxia. PG - e21338 LID - 10.1096/fj.202002193R [doi] AB - Pregnancy complications associated with prenatal hypoxia lead to increased placental oxidative stress. Previous studies suggest that prenatal hypoxia can reduce mitochondrial respiratory capacity and mitochondrial fusion, which could lead to placental dysfunction and impaired fetal development. We developed a placenta-targeted treatment strategy using a mitochondrial antioxidant, MitoQ, encapsulated into nanoparticles (nMitoQ) to reduce placental oxidative stress and (indirectly) improve fetal outcomes. We hypothesized that, in a rat model of prenatal hypoxia, nMitoQ improves placental mitochondrial function and promotes mitochondrial fusion in both male and female placentae. Pregnant rats were treated with saline or nMitoQ on gestational day (GD) 15 and exposed to normoxia (21% O(2) ) or hypoxia (11% O(2) ) from GD15-21. On GD21, male and female placental labyrinth zones were collected for mitochondrial respirometry assessments, mitochondrial content, and markers of mitochondrial biogenesis, fusion and fission. Prenatal hypoxia reduced complex IV activity and fusion in male placentae, while nMitoQ improved complex IV activity in hypoxic male placentae. In female placentae, prenatal hypoxia decreased respiration through the S-pathway (complex II) and increased N-pathway (complex I) respiration, while nMitoQ increased fusion in hypoxic female placentae. No changes in mitochondrial content, biogenesis or fission were found. In conclusion, nMitoQ improved placental mitochondrial function in male and female placentae from fetuses exposed to prenatal hypoxia, which may contribute to improved placental function. However, the mechanisms (ie, changes in mitochondrial respiratory capacity and mitochondrial fusion) were distinct between the sexes. Treatment strategies targeted against placental oxidative stress could improve placental mitochondrial function in complicated pregnancies. CI - (c) 2021 Federation of American Societies for Experimental Biology. FAU - Ganguly, Esha AU - Ganguly E AD - Department of Physiology, University of Alberta, Edmonton, AB, Canada. AD - Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, AB, Canada. AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada. FAU - Kirschenman, Raven AU - Kirschenman R AD - Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, AB, Canada. AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada. FAU - Spaans, Floor AU - Spaans F AD - Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, AB, Canada. AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada. FAU - Holody, Claudia D AU - Holody CD AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada. AD - Department of Paediatrics, University of Alberta, Edmonton, AB, Canada. AD - Faculty Saint-Jean, University of Alberta, Edmonton, AB, Canada. FAU - Phillips, Thomas E J AU - Phillips TEJ AD - Dementia Research Institute, Cardiff University, Cardiff, UK. FAU - Case, C Patrick AU - Case CP AD - Musculoskeletal Research Unit, University of Bristol, Bristol, UK. FAU - Cooke, Christy-Lynn M AU - Cooke CM AD - Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, AB, Canada. AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada. FAU - Murphy, Michael P AU - Murphy MP AD - MRC Mitochondrial Biology Unit, Keith Peters Building, University of Cambridge, Cambridge, UK. FAU - Lemieux, Helene AU - Lemieux H AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada. AD - Faculty Saint-Jean, University of Alberta, Edmonton, AB, Canada. AD - Department of Medicine, University of Alberta, Edmonton, AB, Canada. FAU - Davidge, Sandra T AU - Davidge ST AD - Department of Physiology, University of Alberta, Edmonton, AB, Canada. AD - Department of Obstetrics and Gynaecology, University of Alberta, Edmonton, AB, Canada. AD - Women and Children's Health Research Institute, University of Alberta, Edmonton, AB, Canada. LA - eng GR - FS 154313/CIHR/Canada PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210111 PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - 0 (Antioxidants) RN - 0 (Organophosphorus Compounds) RN - 1339-63-5 (Ubiquinone) RN - 47BYS17IY0 (mitoquinone) SB - IM MH - Animals MH - Antioxidants/administration & dosage/pharmacology/*therapeutic use MH - Cell Respiration MH - Female MH - Fetal Hypoxia/*drug therapy MH - Male MH - Mitochondria/*drug effects/metabolism MH - Mitochondrial Dynamics MH - Nanoparticles/*chemistry MH - Organophosphorus Compounds/administration & dosage/pharmacology/*therapeutic use MH - Placenta/*drug effects/metabolism MH - Pregnancy MH - Rats MH - Rats, Sprague-Dawley MH - Sex Factors MH - Ubiquinone/administration & dosage/*analogs & derivatives/pharmacology/therapeutic use OTO - NOTNLM OT - mitochondrial function OT - nMitoQ OT - placenta OT - prenatal hypoxia EDAT- 2021/01/12 06:00 MHDA- 2021/06/25 06:00 CRDT- 2021/01/11 12:22 PHST- 2020/09/23 00:00 [received] PHST- 2020/12/11 00:00 [revised] PHST- 2020/12/17 00:00 [accepted] PHST- 2021/01/12 06:00 [pubmed] PHST- 2021/06/25 06:00 [medline] PHST- 2021/01/11 12:22 [entrez] AID - 10.1096/fj.202002193R [doi] PST - ppublish SO - FASEB J. 2021 Feb;35(2):e21338. doi: 10.1096/fj.202002193R. Epub 2021 Jan 11.