scholarly journals Effects of nitric oxide donors on cybrids harbouring the mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) A3243G mitochondrial DNA mutation

2005 ◽  
Vol 391 (2) ◽  
pp. 191-202 ◽  
Author(s):  
Jagdeep K. Sandhu ◽  
Caroline Sodja ◽  
Kevan Mcrae ◽  
Yan Li ◽  
Peter Rippstein ◽  
...  
Keyword(s):  
Cell Death ◽  
Lactic Acidosis ◽  
Mitochondrial Myopathy ◽  
Mitochondrial Diseases ◽  
Glucose Deprivation ◽  
Oxygen Species ◽  
Energy Status ◽  
Mitochondrial Dna Mutation ◽  
Dna Mutation ◽  
Nitrative Stress

Reactive nitrogen and oxygen species (O2•−, H2O2, NO• and ONOO−) have been strongly implicated in the pathophysiology of neurodegenerative and mitochondrial diseases. In the present study, we examined the effects of nitrosative and/or nitrative stress generated by DETA-NO {(Z)-1-[2-aminoethyl-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate}, SIN-1 (3-morpholinosydnonimine hydrochloride) and SNP (sodium nitroprusside) on U87MG glioblastoma cybrids carrying wt (wild-type) and mutant [A3243G (Ala3243→Gly)] mtDNA (mitochondrial genome) from a patient suffering from MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes). The mutant cybrids had reduced activity of cytochrome c oxidase, significantly lower ATP level and decreased mitochondrial membrane potential. However, endogenous levels of reactive oxygen species were very similar in all cybrids regardless of whether they carried the mtDNA defects or not. Furthermore, the cybrids were insensitive to the nitrosative and/or nitrative stress produced by either DETA-NO or SIN-1 alone. Cytotoxicity, however, was observed in response to SNP treatment and a combination of SIN-1 and glucose-deprivation. The mutant cybrids were significantly more sensitive to these insults compared with the wt controls. Ultrastructural examination of dying cells revealed several characteristic features of autophagic cell death. We concluded that nitrosative and/or nitrative stress alone were insufficient to trigger cytotoxicity in these cells, but cell death was observed with a combination of metabolic and nitrative stress. The vulnerability of the cybrids to these types of injury correlated with the cellular energy status, which were compromised by the MELAS mutation.

Mitochondrial DNA mutation and muscle pathology in mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes

1995 ◽  
Vol 18 (S14) ◽  
pp. S113-S118 ◽  
Author(s):  
Shuji Mita ◽  
Makoto Tokunaga ◽  
Toshihide Kumamoto ◽  
Makoto Uchino ◽  
Ikuya Nonaka ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Lactic Acidosis ◽  
Mitochondrial Myopathy ◽  
Muscle Pathology ◽  
Mitochondrial Dna Mutation ◽  
Dna Mutation

scholarly journals Dynamic derangement in amino acid profile during and after a stroke-like episode in adult-onset mitochondrial disease: a case report

2019 ◽  
Vol 13 (1) ◽  
Author(s):  
Mai Fukuda ◽  
Yoshiro Nagao
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Lactic Acidosis ◽  
Mitochondrial Disease ◽  
Mitochondrial Myopathy ◽  
Mitochondrial Diseases ◽  
Growth Differentiation Factor 15 ◽  
Differentiation Factor ◽  
High Level ◽  
Inherited Diabetes

Abstract Background Maternally inherited diabetes and deafness, and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes are examples of mitochondrial diseases that are relatively common in the adult population. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes are assumed to be associated with decreases in arginine and citrulline. Biomarkers, such as growth differentiation factor-15, were developed to assist in the diagnosis of mitochondrial diseases. Case presentation A 55-year-old Japanese man, an insulin user, presented after a loss of consciousness. A laboratory test showed diabetic ketoacidosis. He and his mother had severe hearing difficulty. Bilateral lesions on magnetic resonance imaging, the presence of seizure, and an elevated ratio of lactate to pyruvate, altogether suggested a diagnosis of mitochondrial disease. Mitochondrial DNA in our patient’s peripheral blood was positive with a 3243A>G mutation, which is the most frequent cause of maternally inherited diabetes and deafness, and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. As a result, maternally inherited diabetes and deafness/mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes was diagnosed. We measured growth differentiation factor-15 and multiple amino acids in his blood, longitudinally during and after the stroke-like episode. Growth differentiation factor-15 was increased to an immeasurably high level on the day of the stroke-like episode. Although his diabetes improved with an increased dose of insulin, the growth differentiation factor-15 level gradually increased, suggesting that his mitochondrial insufficiency did not improve. Multiple amino acid species, including arginine, citrulline, and taurine, showed a decreased level on the day of the episode and a sharp increase the next day. In contrast, the level of aspartic acid increased to an extremely high level on the day of the episode, and decreased gradually thereafter. Conclusions Growth differentiation factor-15 can be used not only for the diagnosis of mitochondrial disease, but as an indicator of its acute exacerbation. A stroke-like episode of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes reflects a drastic derangement of multiple amino acids. The involvement of aspartic acid in the episodes should be explored in future studies.

Central role of lactic acidosis in cancer cell resistance to glucose deprivation-induced cell death

2012 ◽  
Vol 227 (2) ◽  
pp. 189-199 ◽  
Author(s):  
Hao Wu ◽  
Zonghui Ding ◽  
Danqing Hu ◽  
Feifei Sun ◽  
Chunyan Dai ◽  
...  
Keyword(s):  
Cell Death ◽  
Lactic Acidosis ◽  
Cancer Cell ◽  
Glucose Deprivation ◽  
Cell Resistance

scholarly journals Integrated analysis of the involvement of nitric oxide synthesis in mitochondrial proliferation, mitochondrial deficiency and apoptosis in skeletal muscle fibres

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Gabriela Silva Rodrigues ◽  
Rosely Oliveira Godinho ◽  
Beatriz Hitomi Kiyomoto ◽  
Juliana Gamba ◽  
Acary Souza Bulle Oliveira ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mitochondrial Function ◽  
Mitochondrial Diseases ◽  
Integrated Analysis ◽  
Muscle Fibres ◽  
Mitochondrial Content ◽  
Mitochondrial Dna Mutation ◽  
Dna Mutation ◽  
Mitochondrial Abnormalities ◽  
Skeletal Muscle Fibres

Abstract Nitric oxide (NO) is an important signaling messenger involved in different mitochondrial processes but only few studies explored the participation of NO in mitochondrial abnormalities found in patients with genetic mitochondrial deficiencies. In this study we verified whether NO synthase (NOS) activity was altered in different types of mitochondrial abnormalities and whether changes in mitochondrial function and NOS activity could be associated with the induction of apoptosis. We performed a quantitative and integrated analysis of NOS activity in individual muscle fibres of patients with mitochondrial diseases, considering mitochondrial function (cytochrome-c-oxidase activity), mitochondrial content, mitochondrial DNA mutation and presence of apoptotic nuclei. Our results indicated that sarcolemmal NOS activity was increased in muscle fibres with mitochondrial proliferation, supporting the relevance of neuronal NOS in the mitochondrial biogenesis process. Sarcoplasmic NOS activity was reduced in cytochrome-c-oxidase deficient fibres, probably as a consequence of the involvement of NO in the regulation of the respiratory chain. Alterations in NOS activity or mitochondrial abnormalities were not predisposing factors to apoptotic nuclei. Taken together, our results show that NO can be considered a potential molecular target for strategies to increase mitochondrial content and indicate that this approach may not be associated with increased apoptotic events.

scholarly journals High cell density increases glioblastoma cell viability under glucose deprivation via degradation of the cystine/glutamate transporter xCT (SLC7A11)

2020 ◽  
Vol 295 (20) ◽  
pp. 6936-6945 ◽  
Author(s):  
Itsuki Yamaguchi ◽  
Shige H. Yoshimura ◽  
Hironori Katoh
Keyword(s):  
Cell Death ◽  
Cell Viability ◽  
Cell Density ◽  
High Cell Density ◽  
Glutamate Transporter ◽  
Glucose Deprivation ◽  
Oxygen Species ◽  
Bafilomycin A1 ◽  
Glioblastoma Cells ◽  
Lysosomal Degradation

The cystine/glutamate transporter system xc− consists of the light-chain subunit xCT (SLC7A11) and the heavy-chain subunit CD98 (4F2hc or SLC3A2) and exchanges extracellular cystine for intracellular glutamate at the plasma membrane. The imported cystine is reduced to cysteine and used for synthesis of GSH, one of the most important antioxidants in cancer cells. Because cancer cells have increased levels of reactive oxygen species, xCT, responsible for cystine–glutamate exchange, is overexpressed in many cancers, including glioblastoma. However, under glucose-limited conditions, xCT overexpression induces reactive oxygen species accumulation and cell death. Here we report that cell survival under glucose deprivation depends on cell density. We found that high cell density (HD) down-regulates xCT levels and increases cell viability under glucose deprivation. We also found that growth of glioblastoma cells at HD inactivates mTOR and that treatment of cells grown at low density with the mTOR inhibitor Torin 1 down-regulates xCT and inhibits glucose deprivation-induced cell death. The lysosome inhibitor bafilomycin A1 suppressed xCT down-regulation in HD-cultured glioblastoma cells and in Torin 1–treated cells grown at low density. Additionally, bafilomycin A1 exposure or ectopic xCT expression restored glucose deprivation–induced cell death at HD. These results suggest that HD inactivates mTOR and promotes lysosomal degradation of xCT, leading to improved glioblastoma cell viability under glucose-limited conditions. Our findings provide evidence that control of xCT protein expression via lysosomal degradation is an important mechanism for metabolic adaptation in glioblastoma cells.

Retinal manifestations in mitochondrial diseases associated with mitochondrial DNA mutation

1998 ◽  
Vol 76 (1) ◽  
pp. 6-13 ◽  
Author(s):  
Yasushi Isashiki ◽  
Masanori Nakagawa ◽  
Norio Ohba ◽  
Kosaku Kamimura ◽  
Yukiko Sakoda ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Diseases ◽  
Mitochondrial Dna Mutation ◽  
Dna Mutation
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