Abstract
Endomembrane specialization allows functional compartmentalization but imposes physical constraints to information flow within the cell. However, the evolution of an endomembrane system was associated with the emergence of contact sites facilitating communication between membrane-bound organelles. Contact sites between the endoplasmic reticulum (ER) and mitochondria are highly conserved in terms of their morphological features but show surprising molecular diversity within and across eukaryote species. ER-mitochondria contact sites are thought to regulate key processes in oncogenesis but their molecular composition remains poorly characterized in mammalian cells. In this study, we investigate the localization of pannexin 2 (Panx2), a membrane channel protein showing tumor-suppressing properties in cancer cells. Using a combination of subcellular fractionation, particle tracking in live-cell, and immunogold electron microscopy, we show that Panx2 localizes at ER-mitochondria contact sites in mammalian cells and sensitizes cells to apoptotic stimuli.
Highlights
Mitochondria are physically and functionally associated with the endoplasmic reticulum (ER)at membrane contact sites (MCSs) referred to as mitochondria-associated ER membranes (MAMs).ER-mitochondria MCSs are involved in lipid metabolism, mitochondrial calcium homeostasis, cellular respiration, mtDNA replication, mitochondrial division, autophagosome formation, and initiation of apoptosis [1,2,3,4,5,6,7,8]
Giorgi and co-workers recently demonstrated that in response to stresses, the tumor suppressor p53 accumulates at ER-mitochondria contacts where it interacts with the sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) pump to promote mitochondrial calcium overload leading to apoptosis [15,16]
While a substantial portion of pannexin 2 (Panx2) was found in fraction # 18 which was not enriched for other organelle markers (Figure 1A), protein profiling of Panx2 co-fractionated with bonafide ER and mitochondrial proteins (Figure 1A,B)
Summary
Mitochondria are physically and functionally associated with the endoplasmic reticulum (ER)at membrane contact sites (MCSs) referred to as mitochondria-associated ER membranes (MAMs).ER-mitochondria MCSs are involved in lipid metabolism, mitochondrial calcium homeostasis, cellular respiration, mtDNA replication, mitochondrial division, autophagosome formation, and initiation of apoptosis [1,2,3,4,5,6,7,8]. Mitochondria are physically and functionally associated with the endoplasmic reticulum (ER). At membrane contact sites (MCSs) referred to as mitochondria-associated ER membranes (MAMs). MCSs constitute important signaling hubs and alterations in ER-mitochondria contacts have been associated with tumor progression and metastasis (reviewed in [9,10,11,12,13,14]). Recent studies have revealed that ER-mitochondria contacts can dynamically recruit oncogenes and tumor suppressors that modulate the bioenergetic demand, metabolism, and survival mechanisms of cancer cells. Giorgi and co-workers recently demonstrated that in response to stresses, the tumor suppressor p53 accumulates at ER-mitochondria contacts where it interacts with the sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) pump to promote mitochondrial calcium overload leading to apoptosis [15,16]. Betz and co-workers have shown that upon stimulation by growth factors, mTORC2 localizes at ER-mitochondria contacts where it phosphorylates and activates Akt [17]
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