Loss of thymidine kinase 2 alters neuronal bioenergetics and leads to neurodegeneration

Bartesaghi, Stefano; Betts-Henderson, Joanne; Cain, Kelvin; Dinsdale, David; Zhou, Xiaoshan; Karlsson, Anna; Salomoni, Paolo; Nicotera, Pierluigi

doi:10.1093/hmg/ddq043

Cited by 36 publications

(38 citation statements)

References 25 publications

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“…2G and Dataset S1). Overall, these data together with NDUFA10 KD experiments show that NPCs, unlike postmitotic neurons (25), are able to activate glycolysis upon inhibition of oxidative metabolism. These metabolic changes correlated with increased growth properties, as, when plated at clonal density in nonadherent conditions, KO NPCs formed larger neurospheres (Fig.…”

Section: Resultsmentioning

confidence: 57%

“…To determine whether these changes could occur also in another model of mitochondrial dysfunction, we used genetically modified NPCs, where oxidative phosphorylation is decreased due to loss of thymidine kinase 2 (TK2), a key component of the salvage pathway for nucleotide biosynthesis within mitochondria (24)(25)(26). TK2 knockout (KO) animals are ataxic and die by postnatal day 15 due to defects in multiple tissues, including brain (24)(25)(26).…”

Section: Resultsmentioning

confidence: 99%

“…TK2 knockout (KO) animals are ataxic and die by postnatal day 15 due to defects in multiple tissues, including brain (24)(25)(26). TK2 deficiency in postmitotic cells results in decreased mtDNA synthesis, in turn leading to diminished expression of mtDNA-encoded ETC components and impaired ETC (24)(25)(26). We isolated NPCs from the SVZ of WT and KO mice (preparation WT1 and KO1; Dataset S1).…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

Bartesaghi

Graziano

Galavotti

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Alterations of mitochondrial metabolism and genomic instability have been implicated in tumorigenesis in multiple tissues. High-grade glioma (HGG), one of the most lethal human neoplasms, displays genetic modifications of Krebs cycle components as well as electron transport chain (ETC) alterations. Furthermore, the p53 tumor suppressor, which has emerged as a key regulator of mitochondrial respiration at the expense of glycolysis, is genetically inactivated in a large proportion of HGG cases. Therefore, it is becoming evident that genetic modifications can affect cell metabolism in HGG; however, it is currently unclear whether mitochondrial metabolism alterations could vice versa promote genomic instability as a mechanism for neoplastic transformation. Here, we show that, in neural progenitor/stem cells (NPCs), which can act as HGG cell of origin, inhibition of mitochondrial metabolism leads to p53 genetic inactivation. Impairment of respiration via inhibition of complex I or decreased mitochondrial DNA copy number leads to p53 genetic loss and a glycolytic switch. p53 genetic inactivation in ETC-impaired neural stem cells is caused by increased reactive oxygen species and associated oxidative DNA damage. ETC-impaired cells display a marked growth advantage in the presence or absence of oncogenic RAS, and form undifferentiated tumors when transplanted into the mouse brain. Finally, p53 mutations correlated with alterations in ETC subunit composition and activity in primary glioma-initiating neural stem cells. Together, these findings provide previously unidentified insights into the relationship between mitochondria, genomic stability, and tumor suppressive control, with implications for our understanding of brain cancer pathogenesis.

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Section: Resultsmentioning

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

Bartesaghi

Graziano

Galavotti

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Mutant mice harbouring a specific mutation (knock-in) were produced to elucidate the tissue-specific effects of TK2 deficiency [224], and were shown to develop encephalomyelopathy with prominent vacuolar changes in the anterior horn of the spinal cord. The TK2 knockout mouse model was also studied [225] demonstrating that loss of TK2 activity leads to a severe ataxic phenotype, accompanied by reduced mtDNA copy number and decreased levels of electron transport chain proteins in the brain. In TK2-deficient cerebellar neurons, these abnormalities are associated with impaired mitochondrial bioenergetic function, aberrant mitochondrial ultrastructure and degeneration of selected neuronal types, suggesting that this may be the mechanisms of neurological impairment in TK2-MDS.…”

Section: Thymidine Kinase 2 Deficiencymentioning

confidence: 99%

Neurological Disorders of Purine and Pyrimidine Metabolism

Micheli

Camici²,

Tozzi³

et al. 2011

CTMC

101

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Purines and pyrimidines, regarded for a long time only as building blocks for nucleic acid synthesis and intermediates in the transfer of metabolic energy, gained increasing attention since genetically determined aberrations in their metabolism were associated clinically with various degrees of mental retardation and/or unexpected and often devastating neurological dysfunction. In most instances the molecular mechanisms underlying neurological symptoms remain undefined. This suggests that nucleotides and nucleosides play fundamental but still unknown roles in the development and function of several organs, in particular central nervous system. Alterations of purine and pyrimidine metabolism affecting brain function are spread along both synthesis (PRPS, ADSL, ATIC, HPRT, UMPS, dGK, TK), and breakdown pathways (5NT, ADA, PNP, GCH, DPD, DHPA, TP, UP), sometimes also involving pyridine metabolism. Explanations for the pathogenesis of disorders may include both cellular and mitochondrial damage: e.g. deficiency of the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase and deoxyguanosine kinase are associated to the most severe pathologies, the former due to an unexplained adverse effect exerted on the development and/or differentiation of dopaminergic neurons, the latter due to impairment of mitochondrial functions. This review gathers the presently known inborn errors of purine and pyrimidine metabolism that manifest neurological syndromes, reporting and commenting on the available hypothesis on the possible link between specific enzymatic alterations and brain damage. Such connection is often not obvious, and though investigated for many years, the molecular basis of most dysfunctions of central nervous system associated to purine and pyrimidine metabolism disorders are still unexplained.

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“…Conversely, age-dependent decline of mitochondrial activity makes neurons vulnerable to environmental and metabolic stress, and it has been largely associated with the onset of Parkinson's and Alzheimer's diseases. Mice that present increased mitochondrial DNA mutations and therefore impairment of the electron transport chain have a shorter life span and display neuronal loss [27,28]. Likewise, flies and mice defective for the zinc carboxypeptidase [29,30], a protein that controls the level of mitochondrial enzymes, or mice with reduced expression of the mitochondrial intermembrane apoptosis-inducing factor [31], which is involved in the stabilization of the electron transport chain, display a reduced life span and an extensive neuronal degeneration.…”

Section: Introductionmentioning

confidence: 99%

Ageing, Neuronal Connectivity and Brain Disorders: An Unsolved Ripple Effect

et al. 2011

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Cognitive decline associated with ageing and age-related disorders emerges as one of the greatest health challenges in the next decades. To date, the molecular mechanisms underlying the onset of neuronal physiological changes in the central nervous system remain unclear. Functional MRI and PET studies have indicated the decline in working memory performance in older adults. Similarly, age-related disorders, such as Alzheimer's disease, are associated with changes in the prefontral cortex and related neural circuitry, which underlines the decline of integrative function between different brain regions. This is mainly attributed to the loss of synaptic connectivity, which is a feature commonly observed in neurodegenerative disorders. In humans, the morphological and functional changes in neurons, such as reduction of spine numbers and synaptic dysfunction, precede the first signs of cognitive decline and likely contribute to pathology progression. Thus, a new scenario emerges in which apparently unrelated diseases present common features, such as the remodelling of neuronal circuitries promoted by ageing. For many years, ageing was considered a process of slow deterioration triggered by accidental environmental factors. Conversely, it is now evident that ageing is a biological process tightly controlled by evolutionary highly conserved signalling pathways. Importantly, genetic mutations that enhance longevity significantly delay the loss of synaptic connectivity and, therefore, the onset of age-related brain disorders. Accordingly, tweaking ageing might be an attractive approach to prevent cognitive decline caused by age-related synaptic dysfunction.

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Loss of thymidine kinase 2 alters neuronal bioenergetics and leads to neurodegeneration

Cited by 36 publications

References 25 publications

Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

Inhibition of oxidative metabolism leads to p53 genetic inactivation and transformation in neural stem cells

Neurological Disorders of Purine and Pyrimidine Metabolism

Ageing, Neuronal Connectivity and Brain Disorders: An Unsolved Ripple Effect

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