Current Understanding of Autophagy in Pregnancy

Akitoshi Nakashima, Sayaka Tsuda, Tae Kusabiraki, Aiko Aoki, Akemi Ushijima, Tomoko Shima, Shi-Bin Cheng, Surendra Sharma, Shigeru Saito, Akitoshi Nakashima, Sayaka Tsuda, Tae Kusabiraki, Aiko Aoki, Akemi Ushijima, Tomoko Shima, Shi-Bin Cheng, Surendra Sharma, Shigeru Saito

Abstract

Autophagy is an evolutionarily conserved process in eukaryotes to maintain cellular homeostasis under environmental stress. Intracellular control is exerted to produce energy or maintain intracellular protein quality controls. Autophagy plays an important role in embryogenesis, implantation, and maintenance of pregnancy. This role includes supporting extravillous trophoblasts (EVTs) that invade the decidua (endometrium) until the first third of uterine myometrium and migrate along the lumina of spiral arterioles under hypoxic and low-nutrient conditions in early pregnancy. In addition, autophagy inhibition has been linked to poor placentation-a feature of preeclamptic placentas-in a placenta-specific autophagy knockout mouse model. Studies of autophagy in human placentas have revealed controversial results, especially with regard to preeclampsia and gestational diabetes mellitus (GDM). Without precise estimation of autophagy flux, wrong interpretation would lead to fixed tissues. This paper presents a review of the role of autophagy in pregnancy and elaborates on the interpretation of autophagy in human placental tissues.

Keywords: Atg7; autophagy; lysosomes; p62/SQSTM1; placenta; preeclampsia; protein aggregation.

Conflict of interest statement

The authors declare no conflict of interests. 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.

Figures

Figure 1
Figure 1
Autophagy cascade. An isolation membrane is merging in cytoplasm via PI3K complex. After elongation of the membrane, the isolation membrane closes and completes the autophagosome, which is formed with double membranes. Finally, the autophagosome forms the autolysosome by fusing with the lysosome and digests the contents the inner membrane. Following with the degradation, autophagy provides matured lysosomes by a recycling of proto-lysosomal membrane components.
Figure 2
Figure 2
Placental autophagy inhibition inducing gestational hypertension and poor placentation. (Left figure) Trophoblast-invasion and vascular remodeling are fundamental for normal placentation (the black arrows indicate the place of invasion and vascular remodeling). Autophagy deficiency impairs the functions of trophoblasts in the trophoblast-specific Atg7 knockout mouse model, resulting in poor placentation (the red “T” bars indicate the inhibition). PlGF mRNA levels, but not sFlt1 mRNA levels, are decreased in the knockout placentas (the red arrow indicates the decrease, and the black arrow indicates the stable). (Right figure) Also, the dams bearing the knockout placentas showed hypertension, but not proteinuria (the red arrow indicates the induction of hypertension by the placenta).

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