Raft-like microdomains play a key role in mitochondrial impairment in lymphoid cells from patients with Huntington's disease

Abstract

Huntington's disease (HD) is a genetic neurodegenerative disease characterized by an exceedingly high number of contiguous glutamine residues in the translated protein, huntingtin (Htt). The primary site of cell toxicity is the nucleus, but mitochondria have been identified as key components of cell damage. The present work has been carried out in immortalized lymphocytes from patients with HD. These cells, in comparison with lymphoid cells from healthy subjects, displayed: i) a redistribution of mitochondria, forming large aggregates; ii) a constitutive hyperpolarization of mitochondrial membrane; and iii) a constitutive alteration of mitochondrial fission machinery, with high apoptotic susceptibility. Moreover, mitochondrial fission molecules, e. g., protein dynamin-related protein 1, as well as Htt, associated with mitochondrial raft-like microdomains, glycosphingolipid-enriched structures detectable in mitochondria. These findings, together with the observation that a ceramide synthase inhibitor and a raft disruptor are capable of impairing the peculiar mitochondrial remodeling in HD cells, suggest that mitochondrial alterations occurring in these cells could be due to raft-mediated defects of mitochondrial fission/fusion machinery.-Ciarlo, L., V. Manganelli, P. Matarrese, T. Garofalo, A. Tinari, L. Gambardella, M. Marconi, M. Grasso, R. Misasi, M. Sorice, and W. Malorni. Raft-like microdomains play a key role in mitochondrial impairment in lymphoid cells from patients with Huntington's disease. J. Lipid Res. 2012. 53: 2057-2068

Evidence for the involvement of GD3 ganglioside in autophagosome formation and maturation

“…In particular, it has been hypothesized that ganglioside-protein interactions, which can be evaluated by different techniques, e.g., FRET analysis and mass spectroscopy, 37,38 could act as regulators of membrane organization and may be implicated in the pathogenesis of human diseases. [39][40][41] Accordingly, by using FRET and coimmunoprecipitation analyses, we provided proof of a direct molecular association between GD3 ganglioside and autophagy determinants, i.e., GD3-LC3 and GD3-LAMP1. Importantly, these results came from analyses performed in freshly isolated nontransformed fibroblasts, where the genomic and metabolic alterations due to the number of subseedings are minimized.…”

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

“…The presence of mutant Htt in mitochondrial raft-like microdomains is closely related to the recruitment in these areas of apoptotic factors belonging to the Bcl-2 family, such as Bak, Bax, and t-Bid and this condition evokes in HD cells an increased susceptibility to apoptotic stimuli. Furthermore, mutant Htt colocalizes with DLP1 and interestingly this colocalization takes place in absence of apoptotic stimuli [136], therefore, mutant Htt is able to attract DLP1 onto outer mitochondrial membrane. Once again the mitochondrial raft-like microdomains play a key role in integrating the toxicity of proteins responsible for neurodegenerative diseases with key factors for mitochondrial function.…”

“…Our group has described in lymphoid cells from HD patients the localization of mutant Htt in the mitochondrial raft-like microdomains [136]. The presence of mutant Htt in mitochondrial raft-like microdomains is closely related to the recruitment in these areas of apoptotic factors belonging to the Bcl-2 family, such as Bak, Bax, and t-Bid and this condition evokes in HD cells an increased susceptibility to apoptotic stimuli.…”

Distinct membrane properties are differentially influenced by cardiolipin content and acyl chain composition in biomimetic membranes

“…In E. coli , CL molecules form macroscopic domains in regions of high curvature, which likely support the recruitment of select proteins for regulation of bacterial division [9]. There is also some discussion of CL domains as having properties akin to lipid rafts (although this is highly debatable since cholesterol levels are low in the inner mitochondrial membranes) [69;70]. The importance of CL microdomains is of relevance during initiation of apoptosis, where caspase 8 is thought to localize to CL microdomains that would be spatially distributed at contact sites between the inner and outer mitochondrial membranes [71].…”