Mitochondrial fission and cristae disruption increase the response of cell models of Huntington's disease to apoptotic stimuli

Costa, Veronica; Giacomello, Marta; Hudec, Roman; Lopreiato, Raffaele; Ermak, Gennady; Lim, Dmitri; Malorni, Walter; Davies, Kelvin J.A.; Carafoli, Ernesto; Scorrano, Luca

doi:10.1002/emmm.201000102

Cited by 239 publications

(220 citation statements)

References 65 publications

(104 reference statements)

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“…A decreased apoptotic susceptibility was also detected in the presence of FB1 and MBC. These observations are in line with our previous studies demonstrating that in HD cells, the fragmented mitochondria are characterized by cristae alterations that are aggravated by apoptotic stimulation and can be corrected by maneuvers that prevent fi ssion and cristae remodelling ( 32,39 ). Finally, as concerns hyperpolarization of MM detected in cells from HD patients, this could represent a sort of "risk factor," also contributing to the high apoptotic susceptibility of these cells ( 39 ).…”

Section: Discussionsupporting

confidence: 89%

“…Thereafter, apoptogenic factors released by mitochondria lead to the apoptosis execution pathway. It has recently been demonstrated that mitochondrial fragmentation and cristae alterations characterize cellular models of HD and participate in their increased susceptibility to apoptosis ( 32 ). Furthermore, very recently, genotype-and timedependent caspase activity abnormalities have been demonstrated in blood cells from HD patients ( 33 ).…”

Section: Mitochondrial Fi Ssion Machinerymentioning

confidence: 99%

“…Furthermore, very recently, genotype-and timedependent caspase activity abnormalities have been demonstrated in blood cells from HD patients ( 33 ). In particular, recent literature on this argument claims that mutant Htt can interact with the mitochondrial Drp1, enhancing GTPase Drp1 enzymatic activity and causing excessive mitochondrial fragmentation and abnormal distribution ( 32,33 ). In neurons, it can lead to defective axonal transport of mitochondria and selective synaptic degeneration ( 34,35 ).…”

Section: Mitochondrial Fi Ssion Machinerymentioning

confidence: 99%

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

Ciarlo

Manganelli

Matarrese

et al. 2012

Journal of Lipid Research

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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

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Section: Discussionsupporting

confidence: 89%

Section: Mitochondrial Fi Ssion Machinerymentioning

confidence: 99%

Section: Mitochondrial Fi Ssion Machinerymentioning

confidence: 99%

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

Ciarlo

Manganelli

Matarrese

et al. 2012

Journal of Lipid Research

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“…In this scenario, AMPK could represent one of the leading actors in modulating metabolic events. 80,81 Indeed, AMPK was found to be abnormally activated in the striatum of a transgenic mouse model of HD (R6/2). 82 Ju et al highlighted that the activation of AMPKα1 in striatal neurons is closely associated with mHtt-induced cell death.…”

Section: Ampk In Hdmentioning

confidence: 99%

AMPK in the central nervous system: physiological roles and pathological implications

Rosso¹,

Fioramonti²,

Fracassi³

et al. 2016

RRB

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5′ AMP-activated protein kinase (AMPK) is considered the master metabolic regulator in all eukaryotes, as it maintains cellular energy homeostasis in a variety of tissues, including the brain. In humans, alterations in AMPK activity can lead to a wide spectrum of metabolic disorders. The relevance of this protein kinase in the pathogenesis of diabetes and metabolic syndrome is now well established. On the contrary, correlations between AMPK and brain physiopathology are still poorly characterized. The aim of this review is to summarize and discuss the current knowledge about the prospective involvement of AMPK in the onset and the progression of different neurological diseases.

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“…The morphology of mitochondria cristae was quantified by measuring the lengths of cristae in a mitochondrion and normalizing the lengths by the area of the mitochondrion using ImageJ Software (NIH, Bethesda, MD, USA; Schneider et al 2012). For comparison, the average ratio of cristae lengths to mitochondrial area in PTC samples with low KSR1 mRNA expression was set to 100% (Costa et al 2010).…”

Section: Em Analysismentioning

confidence: 99%

KSR1 is coordinately regulated with Notch signaling and oxidative phosphorylation in thyroid cancer

Lee¹,

Seol²,

Jeong³

et al. 2015

Journal of Molecular Endocrinology

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Kinase suppressor of RAS1 (KSR1) is a scaffold protein implicated in RAS-mediated RAF activation. However, the molecular function of KSR in papillary thyroid cancer (PTC) is unknown. Thus, this study aimed to characterize the role of KSR1 in patients with PTC. qRT-PCR and immunohistochemistry (IHC) revealed inter-tumor heterogeneities in the expression of KSR1 in PTC tissues. Interestingly, BRAFV600E-positive PTC showed higher KSR1 mRNA expression than BRAFV600E-negative PTC (P!0.001). Gene Set Enrichment Analysis (GSEA) using public repositories showed that high KSR1 expression coordinately upregulated Notch signaling (nominal PZ0.019, false discovery rate (FDR) q-valueZ0.165); this finding was supported by GeneNetwork analysis, indicating that KSR1 expression is positively correlated with NOTCH1 expression (rZ0.677, PZ6.15!10 K9 ). siRNA against KSR1 (siKSR1) significantly decreased ERK phosphorylation induced by BRAFV600E, resulting in reduced expression of NOTCH1 and HES1, targets of Notch signaling. GSEA revealed that high KSR1 expression was also associated with downregulation of genes related to oxidative phosphorylation (OxPhos). Consistent with this, electron microscopy showed that PTCs with high KSR1 expression exhibited structural defects of the mitochondrial cristae. Furthermore, siKSR1-transfected BCPAP and 8505C cells generated fewer colonies in colony-forming assays. In addition, GSEA showed that high expression of KSR2 and connector enhancer of KSR1 (CNKSR1) also coordinately upregulated Notch signaling (KSR2: nominal PZ0.0097, FDR q-valueZ0.154 and CNKSR1: nominal P!0.0001, FDR q-valueZ0.00554), and high CNKSR2 was associated with downregulation of the OxPhos gene set (nominal P!0.0001, FDR q-value !0.0001). In conclusion, KSR1 is coordinately regulated with Notch signaling and OxPhos in PTC, because its scaffold function might be required to sustain the proliferative signaling and metabolic remodeling associated with this type of cancer.

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Mitochondrial fission and cristae disruption increase the response of cell models of Huntington's disease to apoptotic stimuli

Cited by 239 publications

References 65 publications

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

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

AMPK in the central nervous system: physiological roles and pathological implications

KSR1 is coordinately regulated with Notch signaling and oxidative phosphorylation in thyroid cancer

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