Evidence for the participation of CHCHD2/MNRR1, a mitochondrial protein, in spontaneous labor at term and in preterm labor with intra-amniotic infection

Abstract

Objective

Intra-amniotic inflammation (IAI), associated with either microbe (infection) or danger signals (sterile), plays a major role in the pathophysiology of preterm labor and delivery. Coiled-Coil-Helix-Coiled-Coil-Helix Domain Containing 2 (CHCHD2) [also known as Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1)], a mitochondrial protein involved in oxidative phosphorylation and cell survival, is capable of sensing tissue hypoxia and inflammatory signaling. The ability to maintain an appropriate energy balance at the cellular level while adapting to environmental stress is essential for the survival of an organism. Mitochondrial dysfunction has been observed in acute systemic inflammatory conditions, such as sepsis, and is proposed to be involved in sepsis-induced multi-organ failure. The purpose of this study was to determine the amniotic fluid concentrations of CHCHD2/MNRR1 in pregnant women, women at term in labor, and those in preterm labor (PTL) with and without IAI.

Methods

This cross-sectional study comprised patients allocated to the following groups: (1) mid-trimester (n = 16); (2) term in labor (n = 37); (3) term not in labor (n = 22); (4) PTL without IAI who delivered at term (n = 25); (5) PTL without IAI who delivered preterm (n = 47); and (6) PTL with IAI who delivered preterm (n = 53). Diagnosis of IAI (amniotic fluid interleukin-6 concentration ≥2.6 ng/mL) included cases associated with microbial invasion of the amniotic cavity and those of sterile nature (absence of detectable bacteria, using culture and molecular microbiology techniques). Amniotic fluid and maternal plasma CHCHD2/MNRR1 concentrations were determined with a validated and sensitive immunoassay.

Results

(1) CHCHD2/MNRR1 was detectable in all amniotic fluid samples and women at term without labor had a higher amniotic fluid CHCHD2/MNRR1 concentration than those in the mid-trimester (p = 0.003); (2) the amniotic fluid concentration of CHCHD2/MNRR1 in women at term in labor was higher than that in women at term without labor (p = 0.01); (3) women with PTL and IAI had a higher amniotic fluid CHCHD2/MNRR1 concentration than those without IAI, either with preterm (p < 0.001) or term delivery (p = 0.01); (4) women with microbial-associated IAI had a higher amniotic fluid CHCHD2/MNRR1 concentration than those with sterile IAI (p < 0.001); (5) among women with PTL and IAI, the amniotic fluid concentration of CHCHD2/MNRR1 correlated with that of interleukin-6 (Spearman’s Rho = 0.7; p < 0.001); and (6) no correlation was observed between amniotic fluid and maternal plasma CHCHD2/MNRR1 concentrations among women with PTL.

Conclusion

CHCHD2/MNRR1 is a physiological constituent of human amniotic fluid in normal pregnancy, and the amniotic concentration of this mitochondrial protein increases during pregnancy, labor at term, and preterm labor with intra-amniotic infection. Hence, CHCHD2/MNRR1 may be released into the amniotic cavity by dysfunctional mitochondria during microbial-associated IAI.

Keywords:

• Amniotic fluid
• bi-organellar
• inflammation
• parturition
• premature

Acknowledgements

The authors thank Maureen McGerty, M.A., (Wayne State University) for her critical reading of the manuscript and editorial support.

Author 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 Romera, 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.

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, 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. 110605MP2F, 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 amniotic fluid and plasma samples.

Disclosure statement

The authors report no potential conflicts of interest. 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, U.S. Department of Health and Human Services (NICHD/NIH/DHHS); and, in part, with Federal funds from NICHD/NIH/DHHS under Contract No. HHSN275201300006C. Dr. Romero has contributed to this work as part of his official duties as an employee of the United States Federal Government. 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.