Deficiency of the mitochondrial sulfide regulator ETHE1 disturbs cell growth, glutathione level and causes proteome alterations outside mitochondria

Sahebekhtiari, Navid; Fernández‐Guerra, Paula; Nochi, Zahra; Carlsen, Jasper; Bross, Peter; Palmfeldt, Johan

doi:10.1016/j.bbadis.2018.10.035

Cited by 19 publications

(11 citation statements)

References 56 publications

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“…This discrepancy might be because they analyzed cells that had been adhering for more than a day whereas we seeded the cells in microplates pre-coated with poly-D-lysine and measured the respiration directly. On the other hand, this same study described a growth initiation phenotype of ETHE1 deficient cells 50 , which is in line with our data on respiration defect of freshly adhered cells. The decreased respiration found here is further in line with data showing cytochrome c oxidase depletion in Ethe1 −/− mice, and impairment of mitochondrial energetic homeostasis caused by metabolites accumulating in ETHE1 deficiency and MoCD in rat tissues 15,27,28,51 .…”

Section: Discussionsupporting

confidence: 92%

“…The alterations in mitochondrial bioenergetics and dynamics were accompanied by increased superoxide production in all cell lines studied, the first direct demonstration of this finding, and consistent with previous data showing an abnormal proteome and decreased levels of reduced glutathione in ETHE1 deficiency cells, indicating disruption of redox homeostasis 30,50 . Moreover, accumulation of H 2 S and sulfite in induced ETHE1 and MoCo deficiency, respectively, elicits an oxidative stress response in rat brain 27,28,51,62 .…”

Section: Discussionsupporting

confidence: 90%

“…This could be observed despite that previous studies showed reversion of H 2 S-induced inhibition of cytochrome c oxidase activity in ETHE1 deficient fibroblasts when exposed to air 14,49 . Furthermore, a recent article on ETHE1 deficient fibroblasts did not show impairment in mitochondrial respiration 50 . This discrepancy might be because they analyzed cells that had been adhering for more than a day whereas we seeded the cells in microplates pre-coated with poly-D-lysine and measured the respiration directly.…”

Section: Discussionmentioning

confidence: 93%

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ETHE1 and MOCS1 deficiencies: Disruption of mitochondrial bioenergetics, dynamics, redox homeostasis and endoplasmic reticulum-mitochondria crosstalk in patient fibroblasts

Grings

Seminotti

Karunanidhi

et al. 2019

Sci Rep

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Ethylmalonic encephalopathy protein 1 (ETHE1) and molybdenum cofactor (MoCo) deficiencies are hereditary disorders that affect the catabolism of sulfur-containing amino acids. ETHE1 deficiency is caused by mutations in the ETHE1 gene, while MoCo deficiency is due to mutations in one of three genes involved in MoCo biosynthesis ( MOCS1 , MOCS2 and GPHN ). Patients with both disorders exhibit abnormalities of the mitochondrial respiratory chain, among other biochemical findings. However, the pathophysiology of the defects has not been elucidated. To characterize cellular derangements, mitochondrial bioenergetics, dynamics, endoplasmic reticulum (ER)-mitochondria communication, superoxide production and apoptosis were evaluated in fibroblasts from four patients with ETHE1 deficiency and one with MOCS1 deficiency. The effect of JP4-039, a promising mitochondrial-targeted antioxidant, was also tested on cells. Our data show that mitochondrial respiration was decreased in all patient cell lines. ATP depletion and increased mitochondrial mass was identified in the same cells, while variable alterations in mitochondrial fusion and fission were seen. High superoxide levels were found in all cells and were decreased by treatment with JP4-039, while the respiratory chain activity was increased by this antioxidant in cells in which it was impaired. The content of VDAC1 and IP3R, proteins involved in ER-mitochondria communication, was decreased, while DDIT3, a marker of ER stress, and apoptosis were increased in all cell lines. These data demonstrate that previously unrecognized broad disturbances of cellular function are involved in the pathophysiology of ETHE1 and MOCS1 deficiencies, and that reduction of mitochondrial superoxide by JP4-039 is a promising strategy for adjuvant therapy of these disorders.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 93%

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ETHE1 and MOCS1 deficiencies: Disruption of mitochondrial bioenergetics, dynamics, redox homeostasis and endoplasmic reticulum-mitochondria crosstalk in patient fibroblasts

Grings

Seminotti

Karunanidhi

et al. 2019

Sci Rep

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“…ETHE1 is a persulfide dioxygenase essential for cellular sulfide detoxification, and its deficiency will disturb cell growth and cause proteome alterations. [ 31 ] ETHE1 participates in the dynamic balance of mitochondrial metabolism. In addition, ETHE1 binds to nuclear transcriptional factors and translocates to the cytoplasm to inhibit the apoptosis induced by p53.…”

Section: Discussionmentioning

confidence: 99%

Ethylmalonic encephalopathy 1 initiates overactive autophagy in depleted uranium‐induced cytotoxicity in the human embryonic kidney 293 cells

Hao

Huang

Ran

et al. 2020

J Biochem & Molecular Tox

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The kidney is the target of the acute toxicity of depleted uranium (DU). However, the mechanism of DU‐induced cytotoxicity is not clear. The study was to demonstrate the role of autophagy in DU‐induced cytotoxicity and to determine the potential mechanism. We confirmed that after a 4‐h exposure to DU, the autophagic vacuoles and the autophagy marker light chain 3‐II in the human embryonic kidney 293 cells (HEK293) increased, and cytotoxicity decreased by abrogation of excessive autophagy using autophagy inhibitor. We also found activation of nucleus p53 and inhibiting mTOR pathways in DU‐treated HEK293 cells. Meanwhile, ethylmalonic encephalopathy 1 (ETHE1) decreased as the exposure dose of DU increased, with increasing autophagy flux. We suggested that by reducing ETHE1, activation of the p53 pathway, and inhibiting mTOR pathways, DU might induce overactive autophagy, which affected the cytotoxicity. This study will provide a novel therapeutic target for the treatment of DU‐induced cytotoxicity.

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“…COX activity, but not its protein levels, are decreased also in tissues of the first three patients described carrying mutations in SQR, a novel cause of Leigh syndrome [36] . Interestingly, there is no evidence of COX deficiency in CoQ deficiency, perhaps due to less severe accumulation of H 2 S. Fibroblasts from patients with EE have low levels of SQR and GSH, complicating the understanding of the mechanism underlying ETHE1 deficiency [37] , [38] .…”

Section: Impairment Of H 2 S Oxidation In Coq Defimentioning

confidence: 99%

Abnormalities of hydrogen sulfide and glutathione pathways in mitochondrial dysfunction

Quinzii

López

2021

Journal of Advanced Research

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Deficiency of the mitochondrial sulfide regulator ETHE1 disturbs cell growth, glutathione level and causes proteome alterations outside mitochondria

Cited by 19 publications

References 56 publications

ETHE1 and MOCS1 deficiencies: Disruption of mitochondrial bioenergetics, dynamics, redox homeostasis and endoplasmic reticulum-mitochondria crosstalk in patient fibroblasts

ETHE1 and MOCS1 deficiencies: Disruption of mitochondrial bioenergetics, dynamics, redox homeostasis and endoplasmic reticulum-mitochondria crosstalk in patient fibroblasts

Ethylmalonic encephalopathy 1 initiates overactive autophagy in depleted uranium‐induced cytotoxicity in the human embryonic kidney 293 cells

Abnormalities of hydrogen sulfide and glutathione pathways in mitochondrial dysfunction

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