Abstract
Hutchinson-Gilford progeria syndrome (HGPS), a fatal premature aging disease, is caused by a single-nucleotide mutation in the LMNA gene. Previous reports have focused on nuclear phenotypes in HGPS cells, yet the potential contribution of the mitochondria, a key player in normal aging, remains unclear. Using high-resolution microscopy analysis, we demonstrated a significantly increased fraction of swollen and fragmented mitochondria and a marked reduction in mitochondrial mobility in HGPS fibroblast cells. Notably, the expression of PGC-1α, a central regulator of mitochondrial biogenesis, was inhibited by progerin. To rescue mitochondrial defects, we treated HGPS cells with a mitochondrial-targeting antioxidant methylene blue (MB). Our analysis indicated that MB treatment not only alleviated the mitochondrial defects but also rescued the hallmark nuclear abnormalities in HGPS cells. Additional analysis suggested that MB treatment released progerin from the nuclear membrane, rescued perinuclear heterochromatin loss and corrected misregulated gene expression in HGPS cells. Together, these results demonstrate a role of mitochondrial dysfunction in developing the premature aging phenotypes in HGPS cells and suggest MB as a promising therapeutic approach for HGPS.
Highlights
Hutchinson–Gilford progeria syndrome (HGPS) is a rare, autosomal dominant disorder characterized by rapid, premature aging in children (Eriksson et al, 2003; Capell & Collins, 2006; Gordon et al, 2007, 2012)
Our results show that methylene blue (MB) treatment improves the mitochondrial morphology and function and seems to rescue the premature aging phenotypes in HGPS nuclei
The cycling between reduced (MBH2) and oxidized (MB) forms facilitates electron transfer, preventing electron leakage, increasing mitochondrial oxidative phosphorylation, and reducing reactive oxygen species (ROS) overproduction under pathological conditions (Atamna & Kumar, 2010). Based on these previous studies, we examined whether the treatment with MB could alleviate dysfunctional mitochondria and delay premature senescence associated with HGPS cells
Summary
Hutchinson–Gilford progeria syndrome (HGPS) is a rare, autosomal dominant disorder characterized by rapid, premature aging in children (Eriksson et al, 2003; Capell & Collins, 2006; Gordon et al, 2007, 2012). It is caused by a C to T mutation in the 11th exon of the LMNA gene (1824C>T) which leaves the amino acid code unchanged, instead activating a cryptic splice site When used, this splice site removes the last 150 nucleotides from the 11th exon, resulting in an internal 50 amino acid deletion in the lamin A protein (De Sandre-Giovannoli et al, 2003; Eriksson et al, 2003). This splice site removes the last 150 nucleotides from the 11th exon, resulting in an internal 50 amino acid deletion in the lamin A protein (De Sandre-Giovannoli et al, 2003; Eriksson et al, 2003) This deletion interferes with posttranslational processing by removing a key protease cleavage site, leading to Accepted for publication 11 November 2015 permanent farnesylation and aberrant anchorage of the mutant lamin A, termed progerin, to the nuclear membrane (Eriksson et al, 2003; Capell & Collins, 2006). Dysfunctional mitochondria can cause systemic problems, increasing amounts of reactive oxygen species (ROS) and triggering DNA and protein damage (Kirkinezos & Moraes, 2001)
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