Clinical chorioamnionitis at term is characterized by changes in the plasma concentration of CHCHD2/MNRR1, a mitochondrial protein

Abstract

Objective

Mitochondrial dysfunction was observed in acute systemic inflammatory conditions such as sepsis and might be involved in sepsis-induced multi-organ failure. Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 2 (CHCHD2), also known as Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1), a bi-organellar protein located in the mitochondria and the nucleus, is implicated in cell respiration, survival, and response to tissue hypoxia. Recently, the reduction of the cellular CHCHD2/MNRR1 protein, as part of mitochondrial dysfunction, has been shown to play a role in the amplification of inflammatory cytokines in a murine model of lipopolysaccharide-induced systemic inflammation. The aim of this study was to determine whether the plasma concentration of CHCHD2/MNRR1 changed during human normal pregnancy, spontaneous labor at term, and clinical chorioamnionitis at term.

Methods

We conducted a cross-sectional study that included the following groups: 1) non-pregnant women (n = 17); 2) normal pregnant women at various gestational ages from the first trimester until term (n = 110); 3) women at term with spontaneous labor (n = 50); and 4) women with clinical chorioamnionitis at term in labor (n = 25). Plasma concentrations of CHCHD2/MNRR1 were assessed by an enzyme-linked immunosorbent assay.

Results

1) Pregnant women at term in labor with clinical chorioamnionitis had a significantly higher plasma CHCHD2/MNRR1 concentration than those in labor without chorioamnionitis (p = .003); 2) CHCHD2/MNRR1 is present in the plasma of healthy non-pregnant and normal pregnant women without significant differences in its plasma concentrations between the two groups; 3) there was no correlation between maternal plasma CHCHD2/MNRR1 concentration and gestational age at venipuncture; and 4) plasma CHCHD2/MNRR1 concentration was not significantly different in women at term in spontaneous labor compared to those not in labor.

Conclusions

CHCHD2/MNRR1 is physiologically present in the plasma of healthy non-pregnant and normal pregnant women, and its concentration does not change with gestational age and parturition at term. However, plasma CHCHD2/MNRR1 is elevated in women at term with clinical chorioamnionitis. CHCHD2/MNRR1, a novel bi-organellar protein located in the mitochondria and the nucleus, is released into maternal plasma during systemic inflammation.

Keywords:

• Bi-organelle protein
• infection
• intravascular inflammation
• labor
• mitochondrial dysfunction
• pregnancy

Acknowledgements

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

Ethical approval

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 (OH99-CH-N055, 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. 082403MP2F(5R), 075299M1E(R)(RCR), and 103108MP2F(RCR)).

Patient consent

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

Authors’ contributions

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

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

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

Formal analysis: Mariachiara Bosco, Tinnakorn Chaiworapongsa, Adi Tarca.

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

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

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

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 School of Medicine Perinatal Initiative for Maternal, Perinatal and Child Health.