TOM20-mediated transfer of Bcl2 from ER to MAM and mitochondria upon induction of apoptosis

Lisenn Lalier,François M Vallette,Didier Lanoé,Vincent Mignard,Pierre-François Cartron,Marie-Pierre Joalland,Stéphen Manon

doi:10.1038/s41419-021-03471-8

Abstract

In this work, we have explored the subcellular localization of Bcl2, a major antiapoptotic protein. In U251 glioma cells, we found that Bcl2 is localized mainly in the ER and is translocated to MAM and mitochondria upon induction of apoptosis; this mitochondrial transfer was not restricted to the demonstrator cell line, even if cell-specific modulations exist. We found that the Bcl2/mitochondria interaction is controlled by TOM20, a protein that belongs to the protein import machinery of the mitochondrial outer membrane. The expression of a small domain of interaction of TOM20 with Bcl2 potentiates its anti-apoptotic properties, which suggests that the Bcl2–TOM20 interaction is proapoptotic. The role of MAM and TOM20 in Bcl2 apoptotic mitochondrial localization and function has been confirmed in a yeast model in which the ER–mitochondria encounter structure (ERMES) complex (required for MAM stability in yeast) has been disrupted. Bcl2–TOM20 interaction is thus an additional player in the control of apoptosis.

Highlights

IntroductionThe processes of the early stages of apoptosis and its regulations are not completely understood arguably crucial for the understanding of this process and the design of targeted therapies in cancer and degenerative diseases
The processes of the early stages of apoptosis and its regulations are not completely understood arguably crucial for the understanding of this process and the design of targeted therapies in cancer and degenerative diseases.The elusive ER-mitochondria contacts called mitochondria-associated membranes (MAM) have been originally described as important in the reversible connection between ER lipids and mitochondria and in the ER/mitochondria calcium exchange[1]
MAM was visualized in resting U251 by confocal and electron microscopic analyses (Fig. 1A, B) and analyzed by subcellular fractionation (Fig. 1C) to confirm that the crude mitochondria fraction (CM) is composed of mitochondria-associated to MAM; after percoll-gradient centrifugation, MAM were separated from pure mitochondria (PM) (M, Fig. 1C), Fig. 1 Bcl[2] localization during the early phase of apoptosis

Summary

Introduction

The processes of the early stages of apoptosis and its regulations are not completely understood arguably crucial for the understanding of this process and the design of targeted therapies in cancer and degenerative diseases. The elusive ER-mitochondria contacts called mitochondria-associated membranes (MAM) have been originally described as important in the reversible connection between ER lipids and mitochondria and in the ER/mitochondria calcium exchange[1]. MAM has been implicated in the control of several basic or pathological situations beyond lipid or calcium signaling[2]. MAM has been shown to be one of the sites of the formation of autophagosomes[3] and linked to the onset of apoptosis[4]. The mechanisms that link MAM and apoptosis are multiple and currently not completely explored for most of them.

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Results

Conclusion