MtDNA mutation associated with mitochondrial dysfunction in megakaryoblastic leukaemic cells

Piccoli, Cláudia; Ripoli, Maria; Scrima, Rosella; Stanziale, Pietro; Ianni, Mauro Di; Moretti, Lorenzo; Biscottini, B; Carella, Massimo; Boffoli, Domenico; Tabilio, Antonio; Capitanio, Nazzareno

doi:10.1038/leu.2008.69

Cited by 14 publications

(19 citation statements)

References 13 publications

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“…The second most frequently mutated complex is Complex I, which is a major site of electron leakage that leads to the formation of superoxide anions. A previous study reported a potential association between the presence of mtDNA mutation in the ND1 gene of Complex I and the abnormal ROS production in blasts obtained from one patient with megacaryoblastic leukaemia 26 . Patients with mutations in either or both of these complexes had worse overall survival than patients without mutations in these complexes.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Mutations in the Mitochondrial Encoded Electron Transport Chain Complexes in Acute Myeloid Leukemia

Akhtari

Alachkar

2018

Sci Rep

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Acute Myeloid Leukemia is a devastating and heterogeneous, hematological malignancy characterized by the uncontrolled proliferation of undifferentiated myeloid progenitor cells—blasts. Mutations in certain mitochondrial proteins, such as IDH2 have been shown to contribute to leukemogenesis. However, the role of mutations in mitochondrial-encoded Electron Transport Chain (ETC) genes have thus far not been well elucidated in AML. Here, we use TCGA data to characterize mutations in the ETC genes and their association with clinical outcomes in AML. We found that mitochondrial ETC mutations—in Complex I, III, IV and/or V (ATP Synthase)—were present in 8% of patients with AML and were significantly more frequent in older patients. Patients with ETC mutations had worse overall survival than ETC wild type patients (OS: 9.3 vs 20.1 months; p-value: 0.007). Additionally, mutations in either or both Complex I and IV were associated with TP53 mutations (p-value: 0.009), and among TP53 mutated patients, mutations in either or both Complex I and IV were significantly associated with worse overall survival (OS: 0.85 vs 9.4 months; p-value: 0.008). Elucidation of the mechanisms by which ETC mutations contribute to AML pathogenesis and progression would facilitate the development of novel therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Characterization of Mutations in the Mitochondrial Encoded Electron Transport Chain Complexes in Acute Myeloid Leukemia

Akhtari

Alachkar

2018

Sci Rep

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“…Forest elephants have a more compact body stature than their savanna counterparts with one population comparison finding L. cyclotis to be 35–40% shorter than L. africana [44], thus, they consume less oxygen. One study on leukaemic cells linked mutations in the ND1 gene to increased levels of oxygen consumption [45]. Other research on elephants found support for adaptive evolution in OXPHOS proteins that were related to higher brain oxygen consumption in these large animals[18].…”

Section: Discussionmentioning

confidence: 99%

Evidence of Positive Selection in Mitochondrial Complexes I and V of the African Elephant

et al. 2014

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As species evolve, they become adapted to their local environments. Detecting the genetic signature of selection and connecting that to the phenotype of the organism, however, is challenging. Here we report using an integrative approach that combines DNA sequencing with structural biology analyses to assess the effect of selection on residues in the mitochondrial DNA of the two species of African elephants. We detected evidence of positive selection acting on residues in complexes I and V, and we used homology protein structure modeling to assess the effect of the biochemical properties of the selected residues on the enzyme structure. Given the role these enzymes play in oxidative phosphorylation, we propose that the selected residues may contribute to the metabolic adaptation of forest and savanna elephants to their unique habitats.

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“…Clearly, a defective respiratory chain results in mitochondrial ROS release, which not only contributes to triggering of a NF-jB/AP-1-mediated response but may also lead to a vicious cycle of oxidationinduced mutations of mtDNA/nDNA and chromosomal instability (Li and Hong 2012). To this end, it is striking that a high statistical association was observed between mitochondrial disorders and lymphoid malignancies (Mende et al 2007) and that leukemias are among cancers in which mitochondrial dysfunctions and mtDNA mutations are most common (e.g., He et al 2003;Linnartz et al 2004;Piccoli et al 2008;Schildgen et al 2011;Yao et al 2007). In particular, defects in complex I mtDNA-encoded genes were often described (Linnartz et al 2004;Piccoli et al 2008;Schildgen et al 2011).…”

Section: Cancermentioning

confidence: 99%

“…To this end, it is striking that a high statistical association was observed between mitochondrial disorders and lymphoid malignancies (Mende et al 2007) and that leukemias are among cancers in which mitochondrial dysfunctions and mtDNA mutations are most common (e.g., He et al 2003;Linnartz et al 2004;Piccoli et al 2008;Schildgen et al 2011;Yao et al 2007). In particular, defects in complex I mtDNA-encoded genes were often described (Linnartz et al 2004;Piccoli et al 2008;Schildgen et al 2011). Moreover, a recent report by Hashizume et al (2012) demonstrated that mice carrying a mtDNA point mutation in complex I subunit Arch.…”

Section: Cancermentioning

confidence: 99%

Mitochondria as Oxidative Signaling Organelles in T-cell Activation: Physiological Role and Pathological Implications

Kamiński

Röth

Krammer

et al. 2013

Arch. Immunol. Ther. Exp.

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MtDNA mutation associated with mitochondrial dysfunction in megakaryoblastic leukaemic cells

Cited by 14 publications

References 13 publications

Characterization of Mutations in the Mitochondrial Encoded Electron Transport Chain Complexes in Acute Myeloid Leukemia

Characterization of Mutations in the Mitochondrial Encoded Electron Transport Chain Complexes in Acute Myeloid Leukemia

Evidence of Positive Selection in Mitochondrial Complexes I and V of the African Elephant

Mitochondria as Oxidative Signaling Organelles in T-cell Activation: Physiological Role and Pathological Implications

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