Cubic Membranes Formation in Synchronized Human Hepatocellular Carcinoma Cells Reveals a Possible Role as a Structural Antioxidant Defense System in Cell Cycle Progression.

Deqin Kong,Jiangzheng Liu,Qingbiao Zhou,Hua Bai,Rui Liu,Jiaxin Zhang,Chunxu Hai,Wenli Li

doi:10.3389/fcell.2020.617406

Abstract

Cubic membranes (CMs) represent unique biological membrane structures with highly curved three-dimensional periodic minimal surfaces, which have been observed in a wide range of cell types and organelles under various stress conditions (e. g., starvation, virus-infection, and oxidation). However, there are few reports on the biological roles of CMs, especially their roles in cell cycle. Hence, we established a stable cell population of human hepatocellular carcinoma cells (HepG2) of 100% S phase by thymidine treatment, and determined certain parameters in G2 phase released from S phase. Then we found a close relationship between CMs formation and cell cycle, and an increase in reactive oxygen species (ROS) and mitochondrial function. After the synchronization of HepG2 cells were induced, CMs were observed through transmission electron microscope in G2 phase but not in G1, S and M phase. Moreover, the increased ATP production, mitochondrial and intracellular ROS levels were also present in G2 phase, which demonstrated a positive correlation with CMs formation by Pearson correlation analysis. This study suggests that CMs may act as an antioxidant structure in response to mitochondria-derived ROS during G2 phase and thus participate in cell cycle progression.

Highlights

It is universally known that all organisms except viruses have biomembranes
cubic membranes (CMs) are found in many cell types, there still lacks a comprehensive understanding of their biological role
The role of CMs in cell cycle has been of interest since the discovery of CMs in amoeba cells during mitosis in 1965

Summary

Introduction

It is universally known that all organisms except viruses have biomembranes. The emergence of biomembranes, which enable cells to exist independently of environment, is a leap in biological evolution. The formation of cubic mitochondrial cristae in amoeba cells protects them against oxidative damage by enhancing the leakage of H2O2 and reactive oxygen species (ROS) in mitochondria and reducing the sensitivity of membrane lipids to oxidants (Deng et al, 2002). It is found that phospholipids rich in long chain polyunsaturated fatty acids in CMs can preferentially bind with superoxide anions, inhibiting the oxidative damage of RNA induced by ROS (Deng and Almsherqi, 2015). Another role of CMs is a “virus factory” in the host cells infected by virus. Virus infection can lead to rearrangement of cell biomembrane system and induce appearance of CMs, which is likely to provide a protective microenvironment for virus assembly and proliferation (Deng et al, 2010)

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