Mitochondrial Mayhem: How cigarette smoke induces placental dysfunction through MMS19 degradation

Area of Science:

• Reproductive biology
• Toxicology
• Molecular biology

Background:

• Cigarette smoke (CS) adversely affects placental growth and embryo development.
• Mechanisms linking CS exposure to placental dysfunction are not fully understood.

Purpose of the Study:

• Investigate CS impact on trophoblast cell proliferation and regulated cell death (RCD).
• Examine CS interference with iron-sulfur cluster (ISC) proteins and the cytosolic ISC assembly (CIA) pathway.

Main Methods:

• Exposure of rats to passive smoking and HTR-8/Sneo cells to cigarette smoke extract (CSE).
• Analysis of placental tissues, ISC protein levels, CIA pathway components, and cell death markers.
• Molecular docking, gene knockdown (KD) of MMS19, transcriptome analysis, and SMAD pathway assessment.

Main Results:

• CS exposure disrupted the CIA pathway, downregulated ISC proteins, and impaired ISC maturation in rat placentas.
• CSE inhibited trophoblast proliferation, induced autophagy and apoptosis by impairing the CIA pathway and ISC proteins.
• Nicotine and nicotyrine promote autophagic degradation of MMS19, a key CIA component.
• MMS19 KD caused autophagic degradation of ISC proteins, inhibited proliferation, induced mitochondrial dysfunction, ROS accumulation, and cell death.
• SMAD pathway dysregulation mediated MMS19 KD-induced mitochondrial damage.
• Placental tissues from smokers showed disrupted ISC proteins and SMAD pathway.

Conclusions:

• Disruption of the CIA pathway and ISC proteins by CS contributes to placental maldevelopment.
• Targeting the MMS19-SMAD pathway may mitigate adverse pregnancy outcomes from CS exposure.