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

Abstract

Objective

Preeclampsia, one of the most serious obstetric complications, is a heterogenous disorder resulting from different pathologic processes. However, placental oxidative stress and an anti-angiogenic state play a crucial role. Mitochondria are a major source of cellular reactive oxygen species. Abnormalities in mitochondrial structures, proteins, and functions have been observed in the placentae of patients with preeclampsia, thus mitochondrial dysfunction has been implicated in the mechanism of the disease. Mitochondrial nuclear retrograde regulator 1 (MNRR1) is a newly characterized bi-organellar protein with pleiotropic functions. In the mitochondria, this protein regulates cytochrome c oxidase activity and reactive oxygen species production, whereas in the nucleus, it regulates the transcription of a number of genes including response to tissue hypoxia and inflammatory signals. Since MNRR1 expression changes in response to hypoxia and to an inflammatory signal, MNRR1 could be a part of mitochondrial dysfunction and involved in the pathologic process of preeclampsia. This study aimed to determine whether the plasma MNRR1 concentration of women with preeclampsia differed from that of normal pregnant women.

Methods

This retrospective case–control study included 97 women with preeclampsia, stratified by gestational age at delivery into early (<34 weeks, n = 40) and late (≥34 weeks, n = 57) preeclampsia and by the presence or absence of placental lesions consistent with maternal vascular malperfusion (MVM), the histologic counterpart of an anti-angiogenic state. Women with an uncomplicated pregnancy at various gestational ages who delivered at term served as controls (n = 80) and were further stratified into early (n = 25) and late (n = 55) controls according to gestational age at venipuncture. Maternal plasma MNRR1 concentrations were determined by an enzyme-linked immunosorbent assay.

Results

1) Women with preeclampsia at the time of diagnosis (either early or late disease) had a significantly higher median (interquartile range, IQR) plasma MNRR1 concentration than the controls [early preeclampsia: 1632 (924–2926) pg/mL vs. 630 (448–4002) pg/mL, p = .026, and late preeclampsia: 1833 (1441–5534) pg/mL vs. 910 (526–6178) pg/mL, p = .021]. Among women with early preeclampsia, those with MVM lesions in the placenta had the highest median (IQR) plasma MNRR1 concentration among the three groups [with MVM: 2066 (1070–3188) pg/mL vs. without MVM: 888 (812–1781) pg/mL, p = .03; and with MVM vs. control: 630 (448–4002) pg/mL, p = .04]. There was no significant difference in the median plasma MNRR1 concentration between women with early preeclampsia without MVM lesions and those with an uncomplicated pregnancy (p = .3). By contrast, women with late preeclampsia, regardless of MVM lesions, had a significantly higher median (IQR) plasma MNRR1 concentration than women in the control group [with MVM: 1609 (1392–3135) pg/mL vs. control: 910 (526–6178), p = .045; and without MVM: 2023 (1578–8936) pg/mL vs. control, p = .01].

Conclusions

MNRR1, a mitochondrial regulator protein, is elevated in the maternal plasma of women with preeclampsia (both early and late) at the time of diagnosis. These findings may reflect some degree of mitochondrial dysfunction, intravascular inflammation, or other unknown pathologic processes that characterize this obstetrical syndrome.

Keywords:

• CHCHD2
• early preeclampsia
• intravascular inflammation
• late preeclampsia
• maternal vascular malperfusion
• oxidative stress
• placenta
• pregnancy

Acknowledgements

The authors thank Maureen McGerty, MA, (Pregnancy Research Branch, NICHD/NIH/DHHS) for her critical reading of the manuscript and editorial support.

Author contributions

Conceptualization, methodology, validation: Tinnakorn Chaiworapongsa, Roberto Romero, Lawrence Grossman, Siddhesh Aras, Manaphat Suksai, and Mariachiara Bosco.

Data curation, writing, original draft preparation: Manaphat Suksai, Mariachiara Bosco, Tinnakorn Chaiworapongsa, Nardhy Gomez-Lopez, and Adi Tarca.

Visualization, writing, review, and editing: Manaphat Suksai, Eunjung Jung, Arun Meyyazhagan, Marcia Arenas-Hernandez, Francesca Gotsch, Lawrence Grossman, Siddhesh Aras, Piya Chaemsaithong, and Roberto Romero.

Formal analysis: Dereje Gudicha, Tinnakorn Chaiworapongsa, Manaphat Suksai, Adi Tarca.

Resources: Tinnakorn Chaiworapongsa, Roberto Romero, Nardhy Gomez-Lopez, Marcia Arenas-Hernandez.

Supervision: Roberto Romero, Tinnakorn Chaiworapongsa, Adi Tarca, Nardhy Gomez-Lopez.

Each author approved the final version of the manuscript prior to its submission to the Journal.

Ethical Statement

This research complies with the guidelines for human studies and was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The study protocols (OH97-CH-N067, OH98-CH-N001, and OH99-CH-N056) were reviewed and approved by the Institutional Review Board of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services (NICHD/NIH/DHHS) and by the Human Investigation Committee of Wayne State University (IRB Nos.110605MP2F, 082403MP2F(5R), and 103108MP2F(RCR)).

Patient consent

Written informed consent was obtained from the study participants prior to the collection of maternal blood samples.

Disclosure statement

The funders had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, or in the decision to publish the results. Dr. Romero has contributed to this work as part of his official duties as an employee of the United States Federal Government.

Data availability statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author at [email protected] (Dr. Romero).

Additional information

Funding

This research was supported, in part, by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, US Department of Health and Human Services (NICHD/NIH/DHHS); and, in part, with Federal funds from NICHD/NIH/DHHS under Contract No. HHSN275201300006C. Dr. Tarca and Dr. Gomez-Lopez were also supported by the Wayne State University Perinatal Initiative for Maternal, Perinatal and Child Health.