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.
Highlights
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)
Investigating the subcellular mechanisms of this behavior, we found some striking findings in these cells: i) a constitutive hyperpolarization of mitochondrial membrane and a redistribution of mitochondria forming large aggregates, ii) a constitutive relocalization of mitochondrial fission machinery at the mitochondria raft-like domains, and iii) an association of Htt with mitochondrial raft-like microdomains
The mechanisms underlying cell death by apoptosis bring into play a series of morphogenetic changes of mitochondria that contribute to the execution of the death program of the cell
Summary
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 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. 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. The key role of mitochondrial dysfunction seems to be due, or to be associated with, the accumulation of mutant Htt fragments at the mitochondrial membrane [6, 7] This suggested that the mechanisms of cell death that lead to the progression of the disease could rely on metabolic impairment.
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