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Role of mitochondrial raft-like microdomains in the regulation of cell apoptosis

  • THE ROLE OF SPHINGOLIPIDS AND LIPID RAFTS IN DETERMINING CELL FATE
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Abstract

Lipid rafts are envisaged as lateral assemblies of specific lipids and proteins that dissociate and associate rapidly and form functional clusters in cell membranes. These structural platforms are not confined to the plasma membrane; indeed lipid microdomains are similarly formed at subcellular organelles, which include endoplasmic reticulum, Golgi and mitochondria, named raft-like microdomains. In addition, some components of raft-like microdomains are present within ER–mitochondria associated membranes. This review is focused on the role of mitochondrial raft-like microdomains in the regulation of cell apoptosis, since these microdomains may represent preferential sites where key reactions take place, regulating mitochondria hyperpolarization, fission-associated changes, megapore formation and release of apoptogenic factors. These structural platforms appear to modulate cytoplasmic pathways switching cell fate towards cell survival or death. Main insights on this issue derive from some pathological conditions in which alterations of microdomains structure or function can lead to severe alterations of cell activity and life span. In the light of the role played by raft-like microdomains to integrate apoptotic signals and in regulating mitochondrial dynamics, it is conceivable that these membrane structures may play a role in the mitochondrial alterations observed in some of the most common human neurodegenerative diseases, such as Amyotrophic lateral sclerosis, Huntington’s chorea and prion-related diseases. These findings introduce an additional task for identifying new molecular target(s) of pharmacological agents in these pathologies.

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Abbreviations

ALS:

Amyotrophic lateral sclerosis

Bax:

Bcl-2-like protein 4

Bid:

BH3 interacting-domain death agonist

CL:

Cardiolipin

CLIPR-59:

Cytoplasmic linker proteins-59

DAMP:

Danger-associated molecular pattern

DLP1/Drp1:

Dynamin-like protein-1

[D]-PDMP:

(±)-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol hydrochloride

ER:

Endoplasmic reticulum

fALS:

Familial form of ALS

GSK-3b:

Glycogen synthase kinase-3b

HD:

Huntington disease

hFis1:

Mitochondrial fission 1 protein

Htt:

Huntingtin

IP3R-1:

Inositol-1,4,5-tris-phosphate receptor

MAM:

Mitochondria-associated membrane

MßCD:

Methyl ß-cyclodextrin

Mfn2:

Mitofusin-2

OMM:

Outer mitochondrial membrane

OPA1:

Optic Atrophy 1

PrPC :

Cellular prion protein

PrPSc :

Conformationally altered isoform of prionic protein

PTPIP51:

Protein tyrosine phosphatase interacting protein 51

Sig1R:

Sigma1 receptor

SOD1:

Superoxide dismutase 1

t-Bid:

Truncated bid

TDP43:

Transactive response DNA binding protein 43

VAPB:

Vesicle-associated membrane protein-associated protein B

VDAC-1:

Voltage-dependent anion channel-1

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Garofalo, T., Manganelli, V., Grasso, M. et al. Role of mitochondrial raft-like microdomains in the regulation of cell apoptosis. Apoptosis 20, 621–634 (2015). https://doi.org/10.1007/s10495-015-1100-x

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