Dynamics of mitochondrial raft-like microdomains in cell life and death

Abstract

On the basis of the biochemical nature of lipid rafts, composed by glycosphingolipids, cholesterol and signaling proteins, it has been suggested that they are part of the complex framework of subcellular intermixing activities that lead to CD95/Fas-triggered apoptosis. We demonstrated that, following CD95/Fas triggering, cellular prion protein (PrPC), which represents a paradigmatic component of lipid rafts, was redistributed to mitochondrial raft-like microdomains via endoplasmic reticulum (ER)-mitochondria associated membranes (MAM) and microtubular network. Raft-like microdomains appear to be involved in a series of intracellular functions, such as: (1) the membrane “scrambling” that participates in cell death execution pathways, (2) the remodeling of organelles, (3) the recruitment of proteins to the mitochondria; (4) the mitochondrial oxidative phosphorylation and ATP production. In conclusion, we suggest that lipid raft components can exert their regulatory activity in apoptosis execution at three different levels: (1) in the DISC formation at the plasma membrane; (2) in the intracellular redistribution at cytoplasmic organelles, and, (3) in the structural and functional mitochondrial modifications associated with apoptosis execution.

Proteomic Analysis of ABCA1-Null Macrophages Reveals a Role for Stomatin-Like Protein-2 in Raft Composition and Toll-Like Receptor Signaling

“…Multiple prior reports across a variety of cell types, including one by our group in RAW 264.7 macrophages (17) have identified several "mitochondrial" proteins in raft preparations (5-7, 36 -38). While some have suggested that raft-like domains exist in mitochondria (39) or that these proteins represent technical artifact (40), stringent in situ approaches such as microscopy and ϩ/ϩ macrophages were transfected with control nontargeting siRNA or SLP-2 siRNA. Cholesterol efflux to bovine serum albumin or apoA-I was then quantified.…”

Exercise‐induced heart mitochondrial cholesterol depletion influences the inhibition of mitochondrial swelling

“…Changes in the response to Ca 2+ ‐induced mitochondrial swelling may be linked to remodelling of raft‐like microdomains (Ziolkowski et al 2010). Growing evidence suggests that raft‐like microdomains occur in mitochondria and are involved in signalling pathways that control the apoptotic process (Garofalo et al 2005, 2007; Martinez‐Abundis et al 2007; Raimondo et al 2012; Sorice et al 2012). On the contrary, another group has reported that mitochondria do not contain lipid rafts and that lipid rafts do not contain mitochondrial proteins (Zheng et al 2009).…”

“…Rather, according to recently published data, mitochondria‐associated endoplasmic reticulum membranes (MAMs) are intracellular detergent‐resistant lipid raft‐like domains (Area‐Gomez et al 2012; Fujimoto et al 2012). However, in spite of the controversy related to the localization of lipid raft‐like microdomains, these dynamic structures contain protein and lipid components and are associated with mitochondrial contact sites and with mPTP, and are involved in regulation of Ca 2+ signalling, mitochondrial bioenergetics and apoptosis (Rizzuto et al 1999; Voelker, 2005; Fujimoto et al 2012; Sorice et al 2012). It has also been shown that lipids specific to raft‐like microdomains play a crucial role in mPTP regulation (Martinez‐Abundis et al 2007).…”

Ca2+homeostasis dysregulation in Alzheimer's disease: a focus on plasma membrane and cell organelles

“…Ca 2+ liberates from the ER to the mitochondria through the MAM (186). The structure is a lipid-raft-like ER membrane domain (187) where mitochondria are adjacent to the ER at a distance of 10-30 nm (188). IP 3 R of the ER and VDAC in the OMM, bridged through mitochondrial chaperone glucose-regulated protein 75, constitute the core of Ca 2+ -transfer microdomain in the MAM (189,190), whose activation forms a Ca 2+ -rich region close to the IMM and facilitates the mitochondrial Ca 2+ uptake mediated by the MCU (186,191).…”