PYCR1 and PYCR2 Interact and Collaborate with RRM2B to Protect Cells from Overt Oxidative Stress

Kuo, Mei Ling; Lee, Mabel Bin Er; Tang, Michelle; Besten, Willem den; Hu, Shuya; Sweredoski, Michael J.; Hess, Sonja; Chou, Chih Ming; Changou, Chun A.; Su, Mingming; Wang, Jia; Su, Leila; Yen, Yun

doi:10.1038/srep18846

Cited by 67 publications

(72 citation statements)

References 43 publications

(84 reference statements)

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“…28 PYCR isozymes have also been demonstrated to co-localize with the stress response protein, ribonucleotide reductase small subunit B (RRM2B) to prevent cellular injury from oxidative stress. 29 Recently, a role for PYCR2 in cellular apoptosis was suggested in melanoma cells, as PYCR2 knockdown led to decreased proliferative capacity and activation of AMPK/mTOR-induced autophagy. 19 PYCR2 deficiency led to increased apoptosis under oxidative stress when cells with homozygous frameshift mutations were treated with H 2 O 2 , and knockdown of PYCR2 ortholog, pycr1b, in a zebrafish model resulted in smaller head/brain, shorter body, down-tilted tail, and hypomotility.…”

Section: Discussionmentioning

confidence: 99%

PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive

Zaki

Bhat

Sultan³

et al. 2016

Annals of Neurology

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Objective A study was undertaken to characterize the clinical features of the newly described hypomyelinating leukodystrophy type 10 with microcephaly. This is an autosomal recessive disorder mapped to chromosome 1q42.12 due to mutations in PYCR2 gene, encoding an enzyme involved in proline synthesis in mitochondria. Methods From several international clinics, eleven consanguineous families were identified with PYCR2 mutations by whole exome or targeted sequencing, with detailed clinical and radiological phenotyping. Selective mutations from patients were tested for effect on protein function. Results The characteristic clinical presentation of patients with PYCR2 mutations included failure to thrive, microcephaly, craniofacial dysmorphism, progressive psychomotor disability, hyperkinetic movements, and axial hypotonia with variable appendicular spasticity. Patients did not survive beyond the first decade of life. Brain magnetic resonance imaging (MRI) showed global brain atrophy and white matter T2 hyperintensities. Routine serum metabolic profiles were unremarkable. Both nonsense and missense mutations were identified, which impaired protein multimerization. Interpretation PYCR2-related syndrome represents a clinically recognizable condition in which PYCR2 mutations lead to protein dysfunction, not detectable on routine biochemical assessments. Mutations predict a poor outcome, probably as a result of impaired mitochondrial function.

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Section: Discussionmentioning

confidence: 99%

PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive

Zaki

Bhat

Sultan³

et al. 2016

Annals of Neurology

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“…Zaki et al (2016) found evidence that PYCR2 is involved in regulating apoptosis under conditions of oxidative stress, and the protein likely plays a role in maintaining mitochondrial membrane potential. While mitochondrial dysfunction for PYCR1 had been demonstrated by Reversade et al (2009), a combined role for PYCR1 and PYCR2 in protection against oxidative stress was confirmed by Kuo et al (2016). This explains why mitochondrial dysfunction and increased lactate on brain MRS can be observed in PYCR2 deficiency (personal observations).…”

Section: Diagnosismentioning

confidence: 99%

Amino acid synthesis deficiencies

Koning

2017

J of Inher Metab Disea

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In recent years the number of disorders known to affect amino acid synthesis has grown rapidly. Nor is it just the number of disorders that has increased: the associated clinical phenotypes have also expanded spectacularly, primarily due to the advances of next generation sequencing diagnostics. In contrast to the “classical” inborn errors of metabolism in catabolic pathways, in which elevated levels of metabolites are easily detected in body fluids, synthesis defects present with low values of metabolites or, confusingly, even completely normal levels of amino acids. This makes the biochemical diagnosis of this relatively new group of metabolic diseases challenging. Defects in the synthesis pathways of serine metabolism, glutamine, proline and, recently, asparagine have all been reported. Although these amino acid synthesis defects are in unrelated metabolic pathways, they do share many clinical features. In children the central nervous system is primarily affected, giving rise to (congenital) microcephaly, early onset seizures and varying degrees of mental disability. The brain abnormalities are accompanied by skin disorders such as cutis laxa in defects of proline synthesis, collodion-like skin and ichthyosis in serine deficiency, and necrolytic erythema in glutamine deficiency. Hypomyelination with accompanying loss of brain volume and gyration defects can be observed on brain MRI in all synthesis disorders. In adults with defects in serine or proline synthesis, spastic paraplegia and several forms of polyneuropathy with or without intellectual disability appear to be the major symptoms in these late-presenting forms of amino acid disorders. This review provides a comprehensive overview of the disorders in amino acid synthesis.

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“…Atf5, mitochondrial Slc25a47, Pycr1[Fiorese et al, 2016;Kuo et al, 2016;Tan, Ooi, Aw, & Hui, 2004]) and there was an increased activation of genes involved in metabolism of extracellular antioxidants (vitamins B5, A and C) in voles from the CEZ. In the spleen, Hp for haptoglobin, an antioxidant that enhances cells' tolerance to F I G U R E 2 Overview of affected liver metabolic pathways between uncontaminated control and CEZ populations of bank voles.…”

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confidence: 99%

Exposure to environmental radionuclides is associated with altered metabolic and immunity pathways in a wild rodent

et al. 2019

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Wildlife inhabiting environments contaminated by radionuclides face putative detrimental effects of exposure to ionizing radiation, with biomarkers such as an increase in DNA damage and/or oxidative stress commonly associated with radiation exposure. To examine the effects of exposure to radiation on gene expression in wildlife, we conducted a de novo RNA sequencing study of liver and spleen tissues from a rodent, the bank vole Myodes glareolus. Bank voles were collected from the Chernobyl Exclusion Zone (CEZ), where animals were exposed to elevated levels of radionuclides, and from uncontaminated areas near Kyiv, Ukraine. Counter to expectations, we did not observe a strong DNA damage response in animals exposed to radionuclides, although some signs of oxidative stress were identified. Rather, exposure to environmental radionuclides was associated with upregulation of genes involved in lipid metabolism and fatty acid oxidation in the livers – an apparent shift in energy metabolism. Moreover, using stable isotope analysis, we identified that fur from bank voles inhabiting the CEZ had enriched isotope values of nitrogen: such an increase is consistent with increased fatty acid metabolism, but also could arise from a difference in diet or habitat between the CEZ and elsewhere. In livers and spleens, voles inhabiting the CEZ were characterized by immunosuppression, such as impaired antigen processing, and activation of leucocytes involved in inflammatory responses. In conclusion, exposure to low dose environmental radiation impacts pathways associated with immunity and lipid metabolism, potentially as a stress‐induced coping mechanism.

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PYCR1 and PYCR2 Interact and Collaborate with RRM2B to Protect Cells from Overt Oxidative Stress

Cited by 67 publications

References 43 publications

PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive

PYCR2 Mutations cause a lethal syndrome of microcephaly and failure to thrive

Amino acid synthesis deficiencies

Exposure to environmental radionuclides is associated with altered metabolic and immunity pathways in a wild rodent

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