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Original Article

A mitochondrial regulator protein, MNRR1, is elevated in the maternal blood of women with preeclampsia

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Article: 2297158 | Received 29 Jun 2023, Accepted 15 Dec 2023, Published online: 14 Jan 2024

References

  • Erez O, Romero R, Jung E, et al. Preeclampsia and eclampsia: the conceptual evolution of a syndrome. Am J Obstet Gynecol. 2022;226(2s):1–15. doi: 10.1016/j.ajog.2021.12.001.
  • Brown MA, Magee LA, Kenny LC, et al. The hypertensive disorders of pregnancy: ISSHP classification, diagnosis & management recommendations for international practice. Pregnancy Hypertens. 2018;13:291–310. doi: 10.1016/j.preghy.2018.05.004.
  • Gestational Hypertension and Preeclampsia: ACOG Practice Bulletin, Number 222. Obstet Gynecol. 2020;135(6):e237–e260.
  • Say L, Chou D, Gemmill A, et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health. 2014;2(6):e323–e333. doi: 10.1016/S2214-109X(14)70227-X.
  • Executive summary: workshop on preeclampsia, January 25–26, 2021, cosponsored by the society for maternal-Fetal medicine and the preeclampsia foundation. Am J Obstet Gynecol. 2021;225(3):B2–B7.
  • Joseph KS, Boutin A, Lisonkova S, et al. Maternal mortality in the United States: recent trends, current status, and future considerations. Obstet Gynecol. 2021;137(5):763–771. doi: 10.1097/AOG.0000000000004361.
  • Jung E, Romero R, Yeo L, et al. The etiology of preeclampsia. Am J Obstet Gynecol. 2022; 226(2s):S844–S866. doi: 10.1016/j.ajog.2021.11.1356.
  • Roberts JM, Taylor RN, Musci TJ, et al. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol. 1989;161(5):1200–1204. doi: 10.1016/0002-9378(89)90665-0.
  • Hubel CA. Dyslipidemia, iron, and oxidative stress in preeclampsia: assessment of maternal and feto-placental interactions. Semin Reprod Endocrinol. 1998;16(1):75–92. doi: 10.1055/s-2007-1016255.
  • Redman CW, Sacks GP, Sargent IL. Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol. 1999;180(2 Pt 1):499–506. doi: 10.1016/s0002-9378(99)70239-5.
  • Gervasi MT, Chaiworapongsa T, Pacora P, et al. Phenotypic and metabolic characteristics of monocytes and granulocytes in preeclampsia. Am J Obstet Gynecol. 2001;185(4):792–797. doi: 10.1067/mob.2001.117311.
  • Chaiworapongsa T, Romero R, Yoshimatsu J, et al. Soluble adhesion molecule profile in normal pregnancy and pre-eclampsia. J Matern Fetal Neonatal Med. 2002;12(1):19–27. doi: 10.1080/jmf.12.1.19.27.
  • Chaiworapongsa T, Yoshimatsu J, Espinoza J, et al. Evidence of in vivo generation of thrombin in patients with small-for-gestational-age fetuses and pre-eclampsia. J Matern Fetal Neonatal Med. 2002;11(6):362–367. doi: 10.1080/jmf.11.6.362.367.
  • Maynard SE, Min JY, Merchan J, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111(5):649–658. doi: 10.1172/JCI17189.
  • Burton GJ, Yung HW, Cindrova-Davies T, et al. Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia. Placenta. 2009;30 Suppl A(Suppl):S43–S48. doi: 10.1016/j.placenta.2008.11.003.
  • Rodgers GM, Taylor RN, Roberts JM. Preeclampsia is associated with a serum factor cytotoxic to human endothelial cells [in vitro research support, U.S. Gov’t, P.H.S.]. Am J Obstet Gynecol. 1988;159(4):908–914. doi: 10.1016/s0002-9378(88)80169-8.
  • Brosens I, Pijnenborg R, Vercruysse L, et al. The "great obstetrical syndromes" are associated with disorders of deep placentation. Am J Obstet Gynecol. 2011;204(3):193–201. doi: 10.1016/j.ajog.2010.08.009.
  • Hauth JC, Clifton RG, Roberts JM, et al. Maternal insulin resistance and preeclampsia. Am J Obstet Gynecol. 2011;204(4):327.e1-6–327.e6. doi: 10.1016/j.ajog.2011.02.024.
  • Redman CW, Tannetta DS, Dragovic RA, et al. Review: does size matter? Placental debris and the pathophysiology of pre-eclampsia. Placenta. 2012;33(Suppl):S48–S54. doi: 10.1016/j.placenta.2011.12.006.
  • Major HD, Campbell RA, Silver RM, et al. Synthesis of sFlt-1 by platelet-monocyte aggregates contributes to the pathogenesis of preeclampsia. Am J Obstet Gynecol. 2014;210(6):547.e1–7. doi: 10.1016/j.ajog.2014.01.024.
  • Redman CW, Staff AC. Preeclampsia, biomarkers, syncytiotrophoblast stress, and placental capacity. Am J Obstet Gynecol. 2015;213(4 Suppl)S9.e1–S9.e4. doi: 10.1016/j.ajog.2015.08.003.
  • Yung HW, Colleoni F, Dommett E, et al. Noncanonical mitochondrial unfolded protein response impairs placental oxidative phosphorylation in early-onset preeclampsia. Proc Natl Acad Sci U S A. 2019;116(36):18109–18118. doi: 10.1073/pnas.1907548116.
  • Levine L, Habertheuer A, Ram C, et al. Syncytiotrophoblast extracellular microvesicle profiles in maternal circulation for noninvasive diagnosis of preeclampsia. Sci Rep. 2020;10(1):6398. doi: 10.1038/s41598-020-62193-7.
  • Burwick RM, Feinberg BB. Complement activation and regulation in preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome. Am J Obstet Gynecol. 2022;226(2S):S1059–S1070.
  • Aye I, Aiken CE, Charnock-Jones DS, et al. Placental energy metabolism in health and disease-significance of development and implications for preeclampsia. Am J Obstet Gynecol. 2020;226(2S):S928–S944.
  • Stepan H, Hund M, Andraczek T. Combining biomarkers to predict pregnancy complications and redefine preeclampsia: the angiogenic-placental syndrome. Hypertension. 2020;75(4):918–926. doi: 10.1161/HYPERTENSIONAHA.119.13763.
  • Rana S, Burke SD, Karumanchi SA. Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders. Am J Obstet Gynecol. 2022;226(2S):S1019–S1034. doi: 10.1016/j.ajog.2020.10.022.
  • Redman CWG, Staff AC, Roberts JM. Syncytiotrophoblast stress in preeclampsia: the convergence point for multiple pathways. Am J Obstet Gynecol. 2022;226(2s):S907–s927. doi: 10.1016/j.ajog.2020.09.047.
  • Roberts JM, Hubel CA, Taylor RN. Endothelial dysfunction yes, cytotoxicity no!. Am J Obstet Gynecol. 1995;173(3 Pt 1):978–979. doi: 10.1016/0002-9378(95)90393-3.
  • Cindrova-Davies T, Sanders DA, Burton GJ, et al. Soluble FLT1 sensitizes endothelial cells to inflammatory cytokines by antagonizing VEGF receptor-mediated signalling. Cardiovasc Res. 2011;89(3):671–679. doi: 10.1093/cvr/cvq346.
  • Lamarca B. Endothelial dysfunction. An important mediator in the pathophysiology of hypertension during pre-eclampsia. Minerva Ginecol. 2012;64(4):309–320.
  • Sacks GP, Studena K, Sargent K, et al. Normal pregnancy and preeclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis. Am J Obstet Gynecol. 1998;179(1):80–86. doi: 10.1016/s0002-9378(98)70254-6.
  • Gotsch F, Romero R, Friel L, et al. CXCL10/IP-10: a missing link between inflammation and anti-angiogenesis in preeclampsia? J Matern Fetal Neonatal Med. 2007;20(11):777–792. doi: 10.1080/14767050701483298.
  • Boij R, Svensson J, Nilsson-Ekdahl K, et al. Biomarkers of coagulation, inflammation, and angiogenesis are independently associated with preeclampsia. Am J Reprod Immunol. 2012;68(3):258–270. doi: 10.1111/j.1600-0897.2012.01158.x.
  • Kucukgoz Gulec U, Tuncay Ozgunen F, Baris Guzel A, et al. An analysis of C-reactive protein, procalcitonin, and D-dimer in pre-eclamptic patients. Am J Reprod Immunol. 2012;68(4):331–337. doi: 10.1111/j.1600-0897.2012.01171.x.
  • Lau SY, Guild SJ, Barrett CJ, et al. Tumor necrosis factor-alpha, interleukin-6, and interleukin-10 levels are altered in preeclampsia: a systematic review and meta-analysis. Am J Reprod Immunol. 2013;70(5):412–427. doi: 10.1111/aji.12138.
  • Stampalija T, Chaiworapongsa T, Romero R, et al. Maternal plasma concentrations of sST2 and angiogenic/anti-angiogenic factors in preeclampsia. J Matern Fetal Neonatal Med. 2013; Sep26(14):1359–1370. doi: 10.3109/14767058.2013.784256.
  • Romero R, Chaemsaithong P, Tarca AL, et al. Maternal plasma-soluble ST2 concentrations are elevated prior to the development of early and late onset preeclampsia - a longitudinal study. J Matern Fetal Neonatal Med. 2018;31(4):418–432. doi: 10.1080/14767058.2017.1286319.
  • Burwick RM, Lokki AI, Fleming SD, et al. Editorial: innate immunity in normal and adverse pregnancy. Front Immunol. 2021;12:646596. doi: 10.3389/fimmu.2021.646596.
  • Kanninen T, Jung E, Gallo DM, et al. Soluble suppression of tumorigenicity-2 in pregnancy with a small-for-gestational-age fetus and with preeclampsia. J Matern Fetal Neonatal Med. 2023;36(1):2153034. doi: 10.1080/14767058.2022.2153034.
  • Wang Y, Walsh SW. Placental mitochondria as a source of oxidative stress in pre-eclampsia. Placenta. 1998;19(8):581–586. doi: 10.1016/s0143-4004(98)90018-2.
  • Wang Y, Walsh SW. Increased superoxide generation is associated with decreased superoxide dismutase activity and mRNA expression in placental trophoblast cells in pre-eclampsia. Placenta. 2001;22(2–3):206–212. doi: 10.1053/plac.2000.0608.
  • Myatt L, Cui X. Oxidative stress in the placenta. Histochem Cell Biol. 2004;122(4):369–382. doi: 10.1007/s00418-004-0677-x.
  • Moretti M, Phillips M, Abouzeid A, et al. Increased breath markers of oxidative stress in normal pregnancy and in preeclampsia. Am J Obstet Gynecol. 2004; May190(5):1184–1190. doi: 10.1016/j.ajog.2003.11.008.
  • Matsubara K, Matsubara Y, Hyodo S, et al. Role of nitric oxide and reactive oxygen species in the pathogenesis of preeclampsia. J Obstet Gynaecol Res. 2010;36(2):239–247. doi: 10.1111/j.1447-0756.2009.01128.x.
  • Burton GJ, Jauniaux E. Oxidative stress. Best Pract Res Clin Obstet Gynaecol. 2011;25(3):287–299. doi: 10.1016/j.bpobgyn.2010.10.016.
  • Sánchez-Aranguren LC, Prada CE, Riaño-Medina CE, et al. Endothelial dysfunction and preeclampsia: role of oxidative stress. Front Physiol. 2014;5:372. doi: 10.3389/fphys.2014.00372.
  • Schoots MH, Gordijn SJ, Scherjon SA, et al. Oxidative stress in placental pathology. Placenta. 2018;69:153–161. doi: 10.1016/j.placenta.2018.03.003.
  • Marín R, Chiarello DI, Abad C, et al. Oxidative stress and mitochondrial dysfunction in early-onset and late-onset preeclampsia. Biochim Biophys Acta Mol Basis Dis. 2020;11866(12):165961. doi: 10.1016/j.bbadis.2020.165961.
  • Ferreira RC, Fragoso MBT, Bueno NB, et al. Oxidative stress markers in preeclamptic placentas: a systematic review with meta-analysis. Placenta. 2020;99:89–100. doi: 10.1016/j.placenta.2020.07.023.
  • Smith AN, Wang X, Thomas DG, et al. The role of mitochondrial dysfunction in preeclampsia: causative factor or collateral damage? Am J Hypertens. 2021;34(5):442–452. doi: 10.1093/ajh/hpab003.
  • Ogden E, Hildebrand GJ, Page EW. Rise of blood pressure during ischemia of the gravid uterus. Proc Soc Exp Biol Med. 1940;43(1):49–51. doi: 10.3181/00379727-43-11091P.
  • Browne JC, Veall N. The maternal placental blood flow in normotensive and hypertensive women. J Obstet Gynaecol Br Emp. 1953;60(2):141–147. doi: 10.1111/j.1471-0528.1953.tb07668.x.
  • Kumar D. Chronic placental ischemia in relation to toxemias of pregnancy: a preliminary report. Am J Obstet Gynecol. 1962;84(10):1323–1329. doi: 10.1016/S0002-9378(16)35742-8.
  • Berger M, Cavanagh D. Toxemia of pregnancy: the hypertensive effect of acute experimental placental ischemia. Am J Obstet Gynecol. 1963;87(3):293–305. doi: 10.1016/0002-9378(63)90528-3.
  • Lunell NO, Nylund LE, Lewander R, et al. Uteroplacental blood flow in pre-eclampsia measurements with indium-113m and a computer-linked gamma camera. Clin Exp Hypertens B. 1982;1(1):105–117. doi: 10.3109/10641958209037184.
  • Espinoza J, Romero R, Mee Kim Y, et al. Normal and abnormal transformation of the spiral arteries during pregnancy. J Perinat Med. 2006;34(6):447–458. doi: 10.1515/JPM.2006.089.
  • Romero R, Kusanovic JP, Chaiworapongsa T, et al. Placental bed disorders in preterm labor, preterm PROM, spontaneous abortion and abruptio placentae [research support, N.I.H., intramural review]. Best Pract Res Clin Obstet Gynaecol. 2011;25(3):313–327. doi: 10.1016/j.bpobgyn.2011.02.006.
  • Staff AC, Fjeldstad HE, Fosheim IK, et al. Failure of physiological transformation and spiral artery atherosis: their roles in preeclampsia. Am J Obstet Gynecol. 2022;226(2s):S895–S906. doi: 10.1016/j.ajog.2020.09.026.
  • Cindrova-Davies T, Spasic-Boskovic O, Jauniaux E, et al. Nuclear factor-kappa B, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress: effects of antioxidant vitamins. Am J Pathol. 2007;170(5):1511–1520. doi: 10.2353/ajpath.2007.061035.
  • Conrad KP, Benyo DF. Placental cytokines and the pathogenesis of preeclampsia. Am J Reprod Immunol. 1997;37(3):240–249. doi: 10.1111/j.1600-0897.1997.tb00222.x.
  • Keelan JA, Mitchell MD. Placental cytokines and preeclampsia. Front Biosci. 2007;12(1):2706–2727. doi: 10.2741/2266.
  • LaMarca BD, Ryan MJ, Gilbert JS, et al. Inflammatory cytokines in the pathophysiology of hypertension during preeclampsia. Curr Hypertens Rep. 2007;9(6):480–485. doi: 10.1007/s11906-007-0088-1.
  • Rusterholz C, Hahn S, Holzgreve W. Role of placentally produced inflammatory and regulatory cytokines in pregnancy and the etiology of preeclampsia. Semin Immunopathol. 2007;29(2):151–162. doi: 10.1007/s00281-007-0071-6.
  • von Dadelszen P, Magee LA, Roberts JM. Subclassification of preeclampsia. Hypertens Pregnancy. 2003;22(2):143–148. doi: 10.1081/PRG-120021060.
  • Roberts JM, Rich-Edwards JW, McElrath TF, et al. Subtypes of preeclampsia: recognition and determining clinical usefulness. Hypertension. 2021;77(5):1430–1441. doi: 10.1161/HYPERTENSIONAHA.120.14781.
  • Korzeniewski SJ, Romero R, Chaiworapongsa T, et al. Maternal plasma angiogenic index-1 (placental growth factor/soluble vascular endothelial growth factor receptor-1) is a biomarker for the burden of placental lesions consistent with uteroplacental underperfusion: a longitudinal case-cohort study. Am J Obstet Gynecol. 2016;214(5):629.e1–629.e17. doi: 10.1016/j.ajog.2015.11.015.
  • Romero R, Jung E, Chaiworapongsa T, et al. Toward a new taxonomy of obstetrical disease: improved performance of maternal blood biomarkers for the great obstetrical syndromes when classified according to placental pathology. Am J Obstet Gynecol. 2022 Oct;227(4):615.e1–615.e25. doi: 10.1016/j.ajog.2022.04.015.
  • Chaiworapongsa T, Romero R, Gotsch F, et al. Preeclampsia at term can be classified into two clusters with different clinical characteristics and outcomes based on angiogenic biomarkers in maternal blood. Am J Obstet Gynecol. 2023;228(5):569.e1–569.e24. doi: 10.1016/j.ajog.2022.11.001.
  • DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med. 2003;348(26):2656–2668. doi: 10.1056/NEJMra022567.
  • Kühlbrandt W. Structure and function of mitochondrial membrane protein complexes. BMC Biol. 2015;13(1):89. doi: 10.1186/s12915-015-0201-x.
  • Yu E, Mercer J, Bennett M. Mitochondria in vascular disease. Cardiovasc Res. 2012;95(2):173–182. doi: 10.1093/cvr/cvs111.
  • Fisher JJ, Bartho LA, Perkins AV, et al. Placental mitochondria and reactive oxygen species in the physiology and pathophysiology of pregnancy. Clin Exp Pharmacol Physiol. 2020;47(1):176–184. doi: 10.1111/1440-1681.13172.
  • Aras S, Bai M, Lee I, et al. MNRR1 (formerly CHCHD2) is a bi-organellar regulator of mitochondrial metabolism. Mitochondrion. 2015;20:43–51. doi: 10.1016/j.mito.2014.10.003.
  • Grossman LI, Purandare N, Arshad R, et al. MNRR1, a biorganellar regulator of mitochondria. Oxid Med Cell Longev. 2017;2017:6739236. doi: 10.1155/2017/6739236.
  • Purandare N, Somayajulu M, Hüttemann M, et al. The cellular stress proteins CHCHD10 and MNRR1 (CHCHD2): partners in mitochondrial and nuclear function and dysfunction. J Biol Chem. 2018;293(17):6517–6529. doi: 10.1074/jbc.RA117.001073.
  • Aras S, Pak O, Sommer N, et al. Oxygen-dependent expression of cytochrome c oxidase subunit 4-2 gene expression is mediated by transcription factors RBPJ, CXXC5 and CHCHD2. Nucleic Acids Res. 2013;41(4):2255–2266. doi: 10.1093/nar/gks1454.
  • Purandare N, Kunji Y, Xi Y, et al. Lipopolysaccharide induces placental mitochondrial dysfunction in murine and human systems by reducing MNRR1 levels via a TLR4-independent pathway. iScience. 2022;25(11):105342. doi: 10.1016/j.isci.2022.105342.
  • ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Obstet Gynecol. 2002;99(1):159–167.
  • Alexander GR, Himes JH, Kaufman RB, et al. A United States national reference for fetal growth. Obstet Gynecol. 1996;87(2):163–168. doi: 10.1016/0029-7844(95)00386-X.
  • Chaiworapongsa T, Romero R, Erez O, et al. The prediction of fetal death with a simple maternal blood test at 20-24 weeks: a role for angiogenic index-1 (PlGF/sVEGFR-1 ratio). Am J Obstet Gynecol. 2017;217(6):682.e1–682.e13. doi: 10.1016/j.ajog.2017.10.001.
  • Redline RW, Heller D, Keating S, et al. Placental diagnostic criteria and clinical correlation - a workshop report. Placenta. 2005;26 Suppl A:S114–S117. doi: 10.1016/j.placenta.2005.02.009.
  • Khong TY, Mooney EE, Ariel I, et al. Sampling and definitions of placental lesions: Amsterdam placental workshop group consensus statement. Arch Pathol Lab Med. 2016;140(7):698–713. doi: 10.5858/arpa.2015-0225-CC.
  • Karumanchi SA, Bdolah Y. Hypoxia and sFlt-1 in preeclampsia: the "chicken-and-egg" question. Endocrinology. 2004;145(11):4835–4837. doi: 10.1210/en.2004-1028.
  • Berkowitz K, Monteagudo A, Marks F, et al. Mitochondrial myopathy and preeclampsia associated with pregnancy. Am J Obstet Gynecol. 1990;162(1):146–147. doi: 10.1016/0002-9378(90)90837-w.
  • Folgerø T, Storbakk N, Torbergsen T, et al. Mutations in mitochondrial transfer ribonucleic acid genes in preeclampsia. Am J Obstet Gynecol. 1996;174(5):1626–1630. doi: 10.1016/s0002-9378(96)70619-1.
  • Say RE, Whittaker RG, Turnbull HE, et al. Mitochondrial disease in pregnancy: a systematic review. Obstet Med. 2011;4(3):90–94. doi: 10.1258/om.2011.110008.
  • Zsengellér ZK, Rajakumar A, Hunter JT, et al. Trophoblast mitochondrial function is impaired in preeclampsia and correlates negatively with the expression of soluble fms-like tyrosine kinase 1. Pregnancy Hypertens. 2016;6(4):313–319. doi: 10.1016/j.preghy.2016.06.004.
  • Shanklin DR, Sibai BM. Ultrastructural aspects of preeclampsia. II. Mitochondrial changes. Am J Obstet Gynecol. 1990;163(3):943–953. doi: 10.1016/0002-9378(90)91102-i.
  • Shi Z, Long W, Zhao C, et al. Comparative proteomics analysis suggests that placental mitochondria are involved in the development of pre-eclampsia. PLoS One. 2013;8(5):e64351. doi: 10.1371/journal.pone.0064351.
  • Matsubara S, Minakami H, Sato I, et al. Decrease in cytochrome c oxidase activity detected cytochemically in the placental trophoblast of patients with pre-eclampsia. Placenta. 1997;18(4):255–259. doi: 10.1016/s0143-4004(97)80059-8.
  • Furui T, Kurauchi O, Tanaka M, et al. Decrease in cytochrome c oxidase and cytochrome oxidase subunit I messenger RNA levels in preeclamptic pregnancies. Obstet Gynecol. 1994;84(2):283–288.
  • Yu J, Guo X, Chen R, et al. Downregulation of mitofusin 2 in placenta is related to preeclampsia. Biomed Res Int. 2016;2016:6323086. doi: 10.1155/2016/6323086.
  • Zhou X, Han TL, Chen H, et al. Impaired mitochondrial fusion, autophagy, biogenesis and dysregulated lipid metabolism is associated with preeclampsia. Exp Cell Res. 2017;359(1):195–204. doi: 10.1016/j.yexcr.2017.07.029.
  • Muralimanoharan S, Maloyan A, Mele J, et al. MIR-210 modulates mitochondrial respiration in placenta with preeclampsia. Placenta. 2012;33(10):816–823. doi: 10.1016/j.placenta.2012.07.002.
  • Holland O, Dekker Nitert M, Gallo LA, et al. Review: placental mitochondrial function and structure in gestational disorders. Placenta. 2017;54:2–9. doi: 10.1016/j.placenta.2016.12.012.
  • Aydogan Mathyk B, Temel Yuksel I, Tayyar A, et al. Maternal serum mitofusin-2 levels in patients with preeclampsia: the possible role of mitochondrial dysfunction in preeclampsia. J Matern Fetal Neonatal Med. 2020;33(11):1861–1866. doi: 10.1080/14767058.2018.1532497.
  • Qiu C, Hevner K, Enquobahrie DA, et al. A case-control study of maternal blood mitochondrial DNA copy number and preeclampsia risk. Int J Mol Epidemiol Genet. 2012;3(3):237–244.
  • McCarthy C, Kenny LC. Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia. Sci Rep. 2016;6(1):32683. doi: 10.1038/srep32683.
  • Marschalek J, Wohlrab P, Ott J, et al. Maternal serum mitochondrial DNA (mtDNA) levels are elevated in preeclampsia - a matched case-control study. Pregnancy Hypertens. 2018;14:195–199. doi: 10.1016/j.preghy.2018.10.003.
  • Williamson RD, McCarthy FP, Khashan AS, et al. Exploring the role of mitochondrial dysfunction in the pathophysiology of pre-eclampsia. Pregnancy Hypertens. 2018;13:248–253. doi: 10.1016/j.preghy.2018.06.012.
  • Baughman JM, Nilsson R, Gohil VM, et al. A computational screen for regulators of oxidative phosphorylation implicates SLIRP in mitochondrial RNA homeostasis. PLoS Genet. 2009;5(8):e1000590. doi: 10.1371/journal.pgen.1000590.
  • Nayak RR, Kearns M, Spielman RS, et al. Coexpression network based on natural variation in human gene expression reveals gene interactions and functions. Genome Res. 2009;19(11):1953–1962. doi: 10.1101/gr.097600.109.
  • Gene [Internet] Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information. 2004 (cited 2022 Dec 29). Available from: https://www.ncbi.nlm.nih.gov/gene/51142.
  • Cavallaro G. Genome-wide analysis of eukaryotic twin CX9C proteins. Mol Biosyst. 2010;6(12):2459–2470. doi: 10.1039/c0mb00058b.
  • Longen S, Bien M, Bihlmaier K, et al. Systematic analysis of the twin cx(9)c protein family. J Mol Biol. 2009;393(2):356–368. doi: 10.1016/j.jmb.2009.08.041.
  • Aras S, Arrabi H, Purandare N, et al. Abl2 kinase phosphorylates Bi-organellar regulator MNRR1 in mitochondria, stimulating respiration. Biochim Biophys Acta Mol Cell Res. 2017;1864(2):440–448. doi: 10.1016/j.bbamcr.2016.11.029.
  • Funayama M, Ohe K, Amo T, et al. CHCHD2 mutations in autosomal dominant late-onset parkinson’s disease: a genome-wide linkage and sequencing study. Lancet Neurol. 2015;14(3):274–282. doi: 10.1016/S1474-4422(14)70266-2.
  • Shi CH, Mao CY, Zhang SY, et al. CHCHD2 gene mutations in familial and sporadic parkinson’s disease. Neurobiol Aging. 2016;38:217.e9–217.e13. doi: 10.1016/j.neurobiolaging.2015.10.040.
  • Yang X, Zhao Q, An R, et al. Mutational scanning of the CHCHD2 gene in han chinese patients with parkinson’s disease and meta-analysis of the literature. Parkinsonism Relat Disord. 2016;29:42–46. doi: 10.1016/j.parkreldis.2016.05.032.
  • Kee TR, Espinoza Gonzalez P, Wehinger JL, et al. Mitochondrial CHCHD2: disease-associated mutations, physiological functions, and current animal models. Front Aging Neurosci. 2021;13:660843. doi: 10.3389/fnagi.2021.660843.
  • Feyeux M, Bourgois-Rocha F, Redfern A, et al. Early transcriptional changes linked to naturally occurring huntington’s disease mutations in neural derivatives of human embryonic stem cells. Hum Mol Genet. 2012;21(17):3883–3895. doi: 10.1093/hmg/dds216.
  • Shimojima K, Okumura A, Hayashi M, et al. CHCHD2 is down-regulated in neuronal cells differentiated from iPS cells derived from patients with lissencephaly. Genomics. 2015;106(4):196–203. doi: 10.1016/j.ygeno.2015.07.001.
  • Ren Y, Wang X, Guo J, et al. CHCHD2 regulates mitochondrial function and apoptosis of ectopic endometrial stromal cells in the pathogenesis of endometriosis. Reprod Sci. 2022;29(8):2152–2164. doi: 10.1007/s43032-021-00831-9.
  • Song R, Yang B, Gao X, et al. Cyclic adenosine monophosphate response element-binding protein transcriptionally regulates CHCHD2 associated with the molecular pathogenesis of hepatocellular carcinoma. Mol Med Rep. 2015;11(6):4053–4062. doi: 10.3892/mmr.2015.3256.
  • Yao Y, Su J, Zhao L, et al. CHCHD2 promotes hepatocellular carcinoma and indicates poor prognosis of hepatocellular carcinoma patients. J Cancer. 2019;10(27):6822–6828. doi: 10.7150/jca.31158.
  • Li L, Wei Y, To C, et al. Integrated omic analysis of lung cancer reveals metabolism proteome signatures with prognostic impact. Nat Commun. 2014;5(1):5469. doi: 10.1038/ncomms6469.
  • Wei Y, Vellanki RN, Coyaud É, et al. CHCHD2 is coamplified with EGFR in NSCLC and regulates mitochondrial function and cell migration. Mol Cancer Res. 2015;13(7):1119–1129. doi: 10.1158/1541-7786.MCR-14-0165-T.
  • Yin X, Xia J, Sun Y, et al. CHCHD2 is a potential prognostic factor for NSCLC and is associated with HIF-1a expression. BMC Pulm Med. 2020;20(1):40. doi: 10.1186/s12890-020-1079-0.
  • Aras S, Maroun MC, Song Y, et al. Mitochondrial autoimmunity and MNRR1 in breast carcinogenesis. BMC Cancer. 2019;19(1):411. doi: 10.1186/s12885-019-5575-7.
  • Bosco M, Romero R, Gallo DM, et al. Clinical chorioamnionitis at term is characterized by changes in the plasma concentration of CHCHD2/MNRR1, a mitochondrial protein. J Matern Fetal Neonatal Med. 2023;36(2):2222333. doi: 10.1080/14767058.2023.2222333.
  • Chaiworapongsa T, Chaemsaithong P, Yeo L, et al. Pre-eclampsia part 1: current understanding of its pathophysiology. Nat Rev Nephrol. 2014;10(8):466–480. doi: 10.1038/nrneph.2014.102.
  • Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350(7):672–683. doi: 10.1056/NEJMoa031884.
  • Chaiworapongsa T, Romero R, Kim YM, et al. Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia. J Matern Fetal Neonatal Med. 2005;17(1):3–18. doi: 10.1080/14767050400028816.
  • Moore Simas TA, Crawford SL, Solitro MJ, et al. Angiogenic factors for the prediction of preeclampsia in high-risk women. Am J Obstet Gynecol. 2007;197(3):244.e1–244.e8. doi: 10.1016/j.ajog.2007.06.030.
  • Stepan H, Unversucht A, Wessel N, et al. Predictive value of maternal angiogenic factors in second trimester pregnancies with abnormal uterine perfusion. Hypertension. 2007;49(4):818–824. doi: 10.1161/01.HYP.0000258404.21552.a3.
  • Romero R, Nien JK, Espinoza J, et al. A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate. J Matern Fetal Neonatal Med. 2008;21(1):9–23. doi: 10.1080/14767050701830480.
  • Powers RW, Jeyabalan A, Clifton RG, et al. Soluble fms-Like tyrosine kinase 1 (sFlt1), endoglin and placental growth factor (PlGF) in preeclampsia among high risk pregnancies. PLoS One. 2010;5(10):e13263. doi: 10.1371/journal.pone.0013263.
  • Khalil A, Maiz N, Garcia-Mandujano R, et al. Longitudinal changes in maternal serum placental growth factor and soluble fms-like tyrosine kinase-1 in women at increased risk of pre-eclampsia. Ultrasound Obstet Gynecol. 2016;47(3):324–331. doi: 10.1002/uog.15750.
  • Chaiworapongsa T, Romero R, Espinoza J, et al. Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia. Young investigator award. Am J Obstet Gynecol. 2004;190(6):1541–1547. doi: 10.1016/j.ajog.2004.03.043.
  • Vaisbuch E, Whitty JE, Hassan SS, et al. Circulating angiogenic and antiangiogenic factors in women with eclampsia. Am J Obstet Gynecol. 2011;204(2):152.e1–152.e9. doi: 10.1016/j.ajog.2010.08.049.
  • Verlohren S, Herraiz I, Lapaire O, et al. New gestational phase-specific cutoff values for the use of the soluble fms-like tyrosine kinase-1/placental growth factor ratio as a diagnostic test for preeclampsia. Hypertension. 2014;63(2):346–352. doi: 10.1161/HYPERTENSIONAHA.113.01787.
  • Chaiworapongsa T, Romero R, Savasan ZA, et al. Maternal plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in patients presenting to the obstetrical triage area with the suspicion of preeclampsia. J Matern Fetal Neonatal Med. 2011;24(10):1187–1207. doi: 10.3109/14767058.2011.589932.
  • Rana S, Powe CE, Salahuddin S, et al. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia. Circulation. 2012;125(7):911–919. doi: 10.1161/CIRCULATIONAHA.111.054361.
  • Chappell LC, Duckworth S, Seed PT, et al. Diagnostic accuracy of placental growth factor in women with suspected preeclampsia: a prospective multicenter study. Circulation. 2013;128(19):2121–2131. doi: 10.1161/CIRCULATIONAHA.113.003215.
  • Chaiworapongsa T, Romero R, Korzeniewski SJ, et al. Plasma concentrations of angiogenic/anti-angiogenic factors have prognostic value in women presenting with suspected preeclampsia to the obstetrical triage area: a prospective study. J Matern Fetal Neonatal Med. 2014;27(2):132–144. doi: 10.3109/14767058.2013.806905.
  • Zeisler H, Llurba E, Chantraine F, et al. Predictive value of the sFlt-1: plGF ratio in women with suspected preeclampsia. N Engl J Med. 2016;374(1):13–22. doi: 10.1056/NEJMoa1414838.
  • Salahuddin S, Wenger JB, Zhang D, et al. KRYPTOR-automated angiogenic factor assays and risk of preeclampsia-related adverse outcomes. Hypertens Pregnancy. 2016;35(3):330–345. doi: 10.3109/10641955.2016.1148162.
  • Sovio U, Gaccioli F, Cook E, et al. Prediction of preeclampsia using the soluble fms-Like tyrosine kinase 1 to placental growth factor ratio: a prospective cohort study of unselected nulliparous women. Hypertension. 2017;69(4):731–738. doi: 10.1161/HYPERTENSIONAHA.116.08620.
  • Barton JR, Woelkers DA, Newman RB, et al. Placental growth factor predicts time to delivery in women with signs or symptoms of early preterm preeclampsia: a prospective multicenter study. Am J Obstet Gynecol. 2020;222(3):259.e1–259.e11. doi: 10.1016/j.ajog.2019.09.003.
  • Binder J, Kalafat E, Palmrich P, et al. Angiogenic markers and their longitudinal change for predicting adverse outcomes in pregnant women with chronic hypertension. Am J Obstet Gynecol. 2021;225(3):305.e1–305.e14. doi: 10.1016/j.ajog.2021.03.041.
  • Dröge LA, Perschel FH, Stütz N, et al. Prediction of preeclampsia-Related adverse outcomes with the sFlt-1 (soluble fms-Like tyrosine kinase 1)/PlGF (placental growth factor)-ratio in the clinical routine: a Real-World study. Hypertension. 2021;77(2):461–471. doi: 10.1161/HYPERTENSIONAHA.120.15146.
  • Dathan-Stumpf A, Czarnowsky V, Hein V, et al. Real-world data on the clinical use of angiogenic factors in pregnancies with placental dysfunction. Am J Obstet Gynecol. 2022;226(2S):S1037–S1047. doi: 10.1016/j.ajog.2020.10.028.
  • Jiang Z, Zou Y, Ge Z, et al. A role of sFlt-1 in oxidative stress and apoptosis in human and mouse Pre-Eclamptic trophoblasts. Biol Reprod. 2015;93(3):73. doi: 10.1095/biolreprod.114.126227.
  • Vaka VR, McMaster KM, Cunningham MW, Jr., et al. Role of mitochondrial dysfunction and reactive oxygen species in mediating hypertension in the reduced uterine perfusion pressure rat model of preeclampsia. Hypertension. 2018;72(3):703–711. doi: 10.1161/HYPERTENSIONAHA.118.11290.
  • Vishnyakova PA, Volodina MA, Tarasova NV, et al. Mitochondrial role in adaptive response to stress conditions in preeclampsia. Sci Rep. 2016;6(1):32410. doi: 10.1038/srep32410.
  • Broady AJ, Loichinger MH, Ahn HJ, et al. Protective proteins and telomere length in placentas from patients with pre-eclampsia in the last trimester of gestation. Placenta. 2017;50:44–52. doi: 10.1016/j.placenta.2016.12.018.
  • Holland OJ, Cuffe JSM, Dekker Nitert M, et al. Placental mitochondrial adaptations in preeclampsia associated with progression to term delivery. Cell Death Dis. 2018;9(12):1150. doi: 10.1038/s41419-018-1190-9.
  • Rana S, Schnettler WT, Powe C, et al. Clinical characterization and outcomes of preeclampsia with normal angiogenic profile. Hypertens Pregnancy. 2013;32(2):189–201. doi: 10.3109/10641955.2013.784788.
  • Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science. 2005;308(5728):1592–1594. doi: 10.1126/science.1111726.
  • Ogge G, Chaiworapongsa T, Romero R, et al. Placental lesions associated with maternal underperfusion are more frequent in early-onset than in late-onset preeclampsia. J Perinat Med. 2011;39(6):641–652. doi: 10.1515/jpm.2011.098.