Mitochondrial-dependent apoptosis in Huntington's disease human cybrids

Ferreira, Ildete L.; Nascimento, Maria V.; Ribeiro, Márcio; Almeida, Sandra; Cardoso, Sandra M.; Grazina, Manuela; Pratas, João; Santos, Maria João; Januário, Cristina; Oliveira, Catarina R.; Rego, A. Cristina

doi:10.1016/j.expneurol.2010.01.002

Cited by 54 publications

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“…In addition, we previously found that HD cybrids, obtained from the fusion of HD platelets with NT2 rho0 cells, depleted of mitochondrial DNA, do not exhibit significant modifications in the activity of mitochondrial respiratory chain complexes I-IV or in mtDNA sequence variations, suggestive of a primary role in mitochondrial susceptibility in the subpopulation of HD carriers studied (Ferreira et al, 2010). In accordance, Swerdlow et al (1999) showed that HD cybrids did not present changes in mitochondrial respiratory chain activity, oxidative stress or calcium homeostasis.…”

Section: Introductionmentioning

confidence: 87%

“…Cybrid production, culture and incubation with 3-NP Cybrids (cytoplasmic hybrid systems) were produced after fusion of mitochondrial DNA-depleted human teratocarcinoma cells (rho0 NT2 cells, obtained from Dr. R. H. Swerdlow, University of Virginia, Charlottesville, VA, USA), with human platelets isolated from six genetically and clinically confirmed HD patients (42-44 CAG repeats) from pre-identified Portuguese families and three age-matched healthy controls (without any neurological disease) as described in Ferreira et al (2010). Cybrids were cultured in Opti-MEM medium supplemented with 10% fetal calf serum, penicillin (100 U/ml), streptomycin (100 μg/ml) and maintained at 37°C in humidified incubator containing 95% air and 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…Cybrids were cultured in Opti-MEM medium supplemented with 10% fetal calf serum, penicillin (100 U/ml), streptomycin (100 μg/ml) and maintained at 37°C in humidified incubator containing 95% air and 5% CO 2 . Experiments were performed with cybrids less than 2 months in culture, as previously described by us (Ferreira et al, 2010). In experiments aiming to inhibit glycolysis, the commonly used culture medium (Opti-MEM) was replaced by RPMI medium with (+Gluc) or without glucose.…”

Section: Methodsmentioning

confidence: 99%

“…Conversely, increased mitochondrial Bim and Bak levels, and a slight release of cytochrome c in untreated HD cybrids explained their moderate susceptibility to mitochondrial-dependent apoptosis (Ferreira et al, 2010). These changes were translated into increased susceptibility of HD cybrids to undergo mitochondrial-dependent apoptosis when subjected to complex II inhibition with 3-nitropropionic acid (3-NP) or to apoptosis elicited by the classic inducer staurosporine (Ferreira et al, 2010). Despite unchanged activity of mitochondrial complexes, this cell model presented evidences of mitochondrial dysfunction based on significant changes on mitochondrial membrane potential and increased ROS generation.…”

Section: Introductionmentioning

confidence: 96%

“…In accordance, Swerdlow et al (1999) showed that HD cybrids did not present changes in mitochondrial respiratory chain activity, oxidative stress or calcium homeostasis. Conversely, increased mitochondrial Bim and Bak levels, and a slight release of cytochrome c in untreated HD cybrids explained their moderate susceptibility to mitochondrial-dependent apoptosis (Ferreira et al, 2010). These changes were translated into increased susceptibility of HD cybrids to undergo mitochondrial-dependent apoptosis when subjected to complex II inhibition with 3-nitropropionic acid (3-NP) or to apoptosis elicited by the classic inducer staurosporine (Ferreira et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Bioenergetic dysfunction in Huntington's disease human cybrids

Ferreira¹,

Cunha‐Oliveira²,

Nascimento³

et al. 2011

Experimental Neurology

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In this work we studied the mitochondrial-associated metabolic pathways in Huntington's disease (HD) versus control (CTR) cybrids, a cell model in which the contribution of mitochondrial defects from patients is isolated. HD cybrids exhibited an interesting increase in ATP levels, when compared to CTR cybrids. Concomitantly, we observed increased glycolytic rate in HD cybrids, as revealed by increased lactate/pyruvate ratio, which was reverted after inhibition of glycolysis. A decrease in glucose-6-phosphate dehydrogenase activity in HD cybrids further indicated decreased rate of the pentose-phosphate pathway. ATP levels of HD cybrids were significantly decreased under glycolysis inhibition, which was accompanied by a decrease in phosphocreatine. Nevertheless, pyruvate supplementation could not recover HD cybrids' ATP or phosphocreatine levels, suggesting a dysfunction in mitochondrial use of that substrate. Oligomycin also caused a decrease in ATP levels, suggesting a partial support of ATP generation by the mitochondria. Nevertheless, mitochondrial NADH/NAD t levels were decreased in HD cybrids, which was correlated with a decrease in pyruvate dehydrogenase activity and protein expression, suggesting decreased tricarboxylic acid cycle (TCA) input from glycolysis. Interestingly, the activity of alpha-ketoglutarate dehydrogenase, a critical enzyme complex that links the TCA to amino acid synthesis and degradation, was increased in HD cybrids. In accordance, mitochondrial levels of glutamate were increased and alanine was decreased, whereas aspartate and glutamine levels were unchanged in HD cybrids. Conversely, malate dehydrogenase activity from total cell extracts was unchanged in HD cybrids. Our results suggest that inherent dysfunction of mitochondria from HD patients affects cellular bioenergetics in an otherwise functional nuclear background.

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Section: Introductionmentioning

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Bioenergetic dysfunction in Huntington's disease human cybrids

Ferreira¹,

Cunha‐Oliveira²,

Nascimento³

et al. 2011

Experimental Neurology

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Blood RNA transcripts reveal similar and differential alterations in fundamental cellular processes in Alzheimer's disease and other neurodegenerative diseases

Huseby

Delvaux

Brokaw

et al. 2022

Alzheimer's & Dementia

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Background Dysfunctional processes in Alzheimer's disease and other neurodegenerative diseases lead to neural degeneration in the central and peripheral nervous system. Research demonstrates that neurodegeneration of any kind is a systemic disease that may even begin outside of the region vulnerable to the disease. Neurodegenerative diseases are defined by the vulnerabilities and pathology occurring in the regions affected. Method A random forest machine learning analysis on whole blood transcriptomes from six neurodegenerative diseases generated unbiased disease‐classifying RNA transcripts subsequently subjected to pathway analysis. Results We report that transcripts of the blood transcriptome selected for each of the neurodegenerative diseases represent fundamental biological cell processes including transcription regulation, degranulation, immune response, protein synthesis, apoptosis, cytoskeletal components, ubiquitylation/proteasome, and mitochondrial complexes that are also affected in the brain and reveal common themes across six neurodegenerative diseases. Conclusion Neurodegenerative diseases share common dysfunctions in fundamental cellular processes. Identifying regional vulnerabilities will reveal unique disease mechanisms. Highlights Transcriptomics offer information about dysfunctional processes. Comparing multiple diseases will expose unique malfunctions within diseases. Blood RNA can be used ante mortem to track expression changes in neurodegenerative diseases. Protocol standardization will make public datasets compatible.

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Apoptosis: why and how does it occur in biology?

Ulukaya

Acılan

Yılmaz³

2011

Cell Biochemistry & Function

188

119

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The literature on apoptosis has grown tremendously in recent years, and the mechanisms that are involved in this programmed cell death pathway have been enlightened. It is now known that apoptosis takes place starting from early development to adult stage for the homeostasis of multicellular organisms, during disease development and in response to different stimuli in many different systems. In this review, we attempted to summarize the current knowledge on the circumstances and the mechanisms that lead to induction of apoptosis, while going over the molecular details of the modulator and mediators of apoptosis as well as drawing the lines between programmed and non-programmed cell death pathways. The review will particularly focus on Bcl-2 family proteins, the role of different caspases in the process of apoptosis, and their inhibitors as well as the importance of apoptosis during different disease states. Understanding the molecular mechanisms involved in apoptosis better will make a big impact on human diseases, particularly cancer, and its management in the clinics.

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Mitochondrial-dependent apoptosis in Huntington's disease human cybrids

Cited by 54 publications

References 50 publications

Bioenergetic dysfunction in Huntington's disease human cybrids

Bioenergetic dysfunction in Huntington's disease human cybrids

Blood RNA transcripts reveal similar and differential alterations in fundamental cellular processes in Alzheimer's disease and other neurodegenerative diseases

Apoptosis: why and how does it occur in biology?

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