MtDNA maintenance and stability genes: MNGIE and mtDNA depletion syndromes

2004 ◽  
pp. 177-200 ◽  
Author(s):  
Michio Hirano ◽  
Ramon Martí ◽  
Maya R. Vilà ◽  
Yutaka Nishigaki
Keyword(s):  
Mtdna Depletion

scholarly journals Ferroptosis: A Combined Model of Human iPSC‐Derived Liver Organoids and Hepatocytes Reveals Ferroptosis in DGUOK Mutant mtDNA Depletion Syndrome (Adv. Sci. 10/2021)

2021 ◽  
Vol 8 (10) ◽  
pp. 2170053
Author(s):  
Jingyi Guo ◽  
Lifan Duan ◽  
Xueying He ◽  
Shengbiao Li ◽  
Yi Wu ◽  
...  
Keyword(s):  
Combined Model ◽  
Mtdna Depletion ◽  
Liver Organoids ◽  
Human Ipsc

scholarly journals Absence of a Universal Mechanism of Mitochondrial Toxicity by Nucleoside Analogs

2007 ◽  
Vol 51 (7) ◽  
pp. 2531-2539 ◽  
Author(s):  
Kaleb C. Lund ◽  
LaRae L. Peterson ◽  
Kendall B. Wallace
Keyword(s):  
Hepg2 Cells ◽  
Nucleoside Analogs ◽  
Cell Types ◽  
Transcriptase Inhibitor ◽  
Positive Control ◽  
H9c2 Cells ◽  
Mtdna Depletion ◽  
Cell Mortality ◽  
Culture Models ◽  
Metabolic Disruption

ABSTRACT Nucleoside analogs are associated with various mitochondrial toxicities, and it is becoming increasingly difficult to accommodate these differences solely in the context of DNA polymerase gamma inhibition. Therefore, we examined the toxicities of zidovudine (AZT) (10 and 50 μM; 2.7 and 13.4 μg/ml), didanosine (ddI) (10 and 50 μM; 2.4 and 11.8 μg/ml), and zalcitabine (ddC) (1 and 5 μM; 0.21 and 1.1 μg/ml) in HepG2 and H9c2 cells without the presumption of mitochondrial DNA (mtDNA) depletion. Ethidium bromide (EtBr) (0.5 μg/ml; 1.3 μM) was used as a positive control. AZT treatment resulted in metabolic disruption (increased lactate and superoxide) and increased cell mortality with decreased proliferation, while mtDNA remained unchanged or increased (HepG2 cells; 50 μM AZT). ddC caused pronounced mtDNA depletion in HepG2 cells but not in H9c2 cells and increased mortality in HepG2 cells, but no significant metabolic disruption in either cell type. ddI caused a moderate depletion of mtDNA in both cell types but showed no other effects. EtBr exposure resulted in metabolic disruption, increased cell mortality with decreased cell proliferation, and mtDNA depletion in both cell types. We conclude that nucleoside analogs display unique toxicities within and between culture models, and therefore, care should be taken when generalizing about the mechanisms of nucleoside reverse transcriptase inhibitor toxicity. Additionally, mtDNA abundance does not necessarily correlate with metabolic disruption, especially in cell culture; careful discernment is recommended in this regard.

Hypertrophic cardiomyopathy and mtDNA depletion. Successful treatment with heart transplantation

2002 ◽  
Vol 12 (1) ◽  
pp. 56-59 ◽  
Author(s):  
F.M. Santorelli ◽  
M.G. Gagliardi ◽  
C. Dionisi-Vici ◽  
F. Parisi ◽  
A. Tessa ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Heart Transplantation ◽  
Successful Treatment ◽  
Mtdna Depletion

102 Yeast homologues of disease mutations in DNA polymerase gamma cause mtDNA depletion and mutagenesis

Mitochondrion ◽  
2010 ◽  
Vol 10 (2) ◽  
pp. 228
Author(s):  
Jeffrey D. Stumpf ◽  
Diana Spell ◽  
Matthew Stillwagon ◽  
Karen S. Anderson ◽  
William C. Copeland
Keyword(s):  
Dna Polymerase ◽  
Polymerase Gamma ◽  
Mtdna Depletion ◽  
Dna Polymerase Gamma ◽  
Disease Mutations

MTO04 Leigh-like encephalomyopathy and mild methylmalonic aciduria: a new MtDNA depletion syndrome

2007 ◽  
Vol 11 ◽  
pp. 19-20
Author(s):  
B.T. Poll-The ◽  
L. Wagener-Schimmel ◽  
N. Abeling ◽  
H. Waterham ◽  
R.J.A. Wanders ◽  
...  
Keyword(s):  
Methylmalonic Aciduria ◽  
Mtdna Depletion

scholarly journals Basic biochemical characterization of cytosolic enzymes in thymidine nucleotide synthesis in adult rat tissues: implications for tissue specific mitochondrial DNA depletion and deoxynucleoside-based therapy for TK2-deficiency

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Liya Wang ◽  
Ren Sun ◽  
Staffan Eriksson
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dna ◽  
Biochemical Characterization ◽  
Basic Knowledge ◽  
Rat Tissues ◽  
Nucleotide Synthesis ◽  
Tissue Specific ◽  
Mtdna Depletion ◽  
Adult Rat ◽  
Mitochondrial Dna Depletion

Abstract Background Deficiency in thymidine kinase 2 (TK2) or p53 inducible ribonucleotide reductase small subunit (p53R2) is associated with tissue specific mitochondrial DNA (mtDNA) depletion. To understand the mechanisms of the tissue specific mtDNA depletion we systematically studied key enzymes in dTMP synthesis in mitochondrial and cytosolic extracts prepared from adult rat tissues. Results In addition to mitochondrial TK2 a cytosolic isoform of TK2 was characterized, which showed similar substrate specificity to the mitochondrial TK2. Total TK activity was highest in spleen and lowest in skeletal muscle. Thymidylate synthase (TS) was detected in cytosols and its activity was high in spleen but low in other tissues. TS protein levels were high in heart, brain and skeletal muscle, which deviated from TS activity levels. The p53R2 proteins were at similar levels in all tissues except liver where it was ~ 6-fold lower. Our results strongly indicate that mitochondria in most tissues are capable of producing enough dTTP for mtDNA replication via mitochondrial TK2, but skeletal muscle mitochondria do not and are most likely dependent on both the salvage and de novo synthesis pathways. Conclusion These results provide important information concerning mechanisms for the tissue dependent variation of dTTP synthesis and explained why deficiency in TK2 or p53R2 leads to skeletal muscle dysfunctions. Furthermore, the presence of a putative cytosolic TK2-like enzyme may provide basic knowledge for the understanding of deoxynucleoside-based therapy for mitochondrial disorders.

scholarly journals Retrospective natural history of thymidine kinase 2 deficiency

2018 ◽  
Vol 55 (8) ◽  
pp. 515-521 ◽  
Author(s):  
Caterina Garone ◽  
Robert W Taylor ◽  
Andrés Nascimento ◽  
Joanna Poulton ◽  
Carl Fratter ◽  
...  
Keyword(s):  
Natural History ◽  
Matrix Protein ◽  
Nuclear Dna ◽  
Late Onset ◽  
Age At Onset ◽  
Neurological Involvement ◽  
Rapid Progression ◽  
Limb Weakness ◽  
Essential Information ◽  
Mtdna Depletion

BackgroundThymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy.ObjectiveTo perform a retrospective natural history study of a large cohort of patients with TK2 deficiency.MethodsThe study was conducted by 42 investigators across 31 academic medical centres.ResultsWe identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate-to-severe progression of generalised weakness and median POS at least 13 years; and (3) late-onset myopathy (17.4%) with mild limb weakness at onset and slow progression to respiratory insufficiency with median POS of 23 years. Ophthalmoparesis and facial weakness are frequent in adults. Muscle biopsies show multiple mtDNA deletions often with mtDNA depletion.ConclusionsIn TK2 deficiency, age at onset, rate of weakness progression and POS are important variables that define three clinical subtypes. Nervous system involvement often complicates the clinical course of the infantile-onset form while extraocular muscle and facial involvement are characteristic of the late-onset form. Our observations provide essential information for planning future clinical trials in this disorder.

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