Fetal and obstetrics manifestations of mitochondrial diseases

Abstract

During embryonic and neonatal development, mitochondria have essential effects on metabolic and energetic regulation, shaping cell fate decisions and leading to significant short- and long-term effects on embryonic and offspring health. Therefore, perturbation on mitochondrial function can have a pathological effect on pregnancy. Several shreds of evidence collected in preclinical models revealed that severe mitochondrial dysfunction is incompatible with life or leads to critical developmental defects, highlighting the importance of correct mitochondrial function during embryo-fetal development. The mechanism impairing the correct development is unknown and may include a dysfunctional metabolic switch in differentiating cells due to decreased ATP production or altered apoptotic signalling. Given the central role of mitochondria in embryonic and fetal development, the mitochondrial dysfunction typical of Mitochondrial Diseases (MDs) should, in principle, be detectable during pregnancy. However, little is known about the clinical manifestations of MDs in embryonic and fetal development. In this manuscript, we review preclinical and clinical evidence suggesting that MDs may affect fetal development and highlight the fetal and maternal outcomes that may provide a wake-up call for targeted genetic diagnosis.

Fig. 1

Schematic representation of the mitochondrial changes during the embryonic stem cell differentiation in somatic cells. Spherical-shaped mitochondria in pluripotent stem cells become elongated in differentiated cells. This process leads to changes in the cell metabolism that switch from glycolysis to OXPHOS

Fig. 2

Embryonic lethality in different MD mouse models usually occurs between E7.5 and E13.5. Adapted from “Mouse Development Embryonic Stages” assembled using dynamic BioRender assets. Retrieved from https://app.biorender.com/biorender-templates/figures/all/t-6009a97e28bf69021fdce6e1-mouse-development-embryonic-stages

Fig. 3

Reported pregnancy complications in women affected by MDS: pre-eclampsia, gestational diabetes, polyhydramnios, oligohydramnios, and premature delivery. See Sect. 3 for details. Created with BioRender.com

Fig. 4

Reported antenatal presentation of MDs: Fetal Growth Restriction (FGR), Subependymal pseudocysts (SEPC), Chronic intestinal pseudo-obstruction (CIPO). See Sect. 3 for details. Created with BioRender.com

Fig. 5

Schematic representation of translational (from preclinical to clinical) AI application for prenatal imaging identification of MDs. Created with BioRender.com