ETHE1 overexpression promotes SIRT1 and PGC1α mediated aerobic glycolysis, oxidative phosphorylation, mitochondrial biogenesis and colorectal cancer

Witherspoon, Mavee; Sandu, Davinder; Lu, Chong‐Dao; Wang, Kehui; Edwards, Robert A.; Yeung, Anthony T.; Gelincik, Ozkan; Manfredi, Giovanni; Gross, Steven S.; Kopelovich, Levy; Lipkin, Steven M.

doi:10.18632/oncotarget.26958

Cited by 19 publications

(13 citation statements)

References 59 publications

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“…For example, Witherspoon et al 14 indicated that the constitutive expression of ETHE1 increases aerobic glycolysis ("Warburg effect"), oxidative phosphorylation, and mitochondrial biogenesis in colorectal cancer (CRC) cell lines. 35 Yang and colleagues 36 suggested that mitochondrial biogenesis and maintenance may play an important part in tumor cell survival during CRC progression. In our study, our data showed that upregulated MCU promotes mitochondrial biogenesis in CRC cells.…”

Section: Discussionmentioning

confidence: 99%

“…MCU-induced mitochondrial Ca 2+ uptake promotes mitochondrial biogenesis in CRC cells Several recent studies have reported the biological role of increased mitochondrial biogenesis in CRC tumorigenesis. 14,15 Therefore, we further explored the correlation between the expression of MCU and mitochondrial biogenesis in CRC cells. As shown in Fig.…”

Section: Upregulation Of Mcu Enhances the Mitochondrial Ca 2+ Uptake mentioning

confidence: 99%

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MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth

Yang

Jin

Wang

et al. 2020

Sig Transduct Target Ther

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Mitochondrial calcium uniporter (MCU) has an important role in regulating mitochondrial calcium (Ca 2+) homeostasis. Dysregulation of mitochondrial Ca 2+ homeostasis has been implicated in various cancers. However, it remains unclear whether MCU regulates mitochondrial Ca 2+ uptake to promote cell growth in colorectal cancer (CRC). Therefore, in the present study the expression of MCU in CRC tissues and its clinical significance were examined. Following which, the biological function of MCUmediated mitochondrial Ca 2+ uptake in CRC cell growth and the underlying mechanisms were systematically evaluated using in in vitro and in vivo assays, which included western blotting, cell viability and apoptosis assays, as well as xenograft nude mice models. Our results demonstrated that MCU was markedly upregulated in CRC tissues at both the mRNA and protein levels. Upregulated MCU was associated with poor prognosis in patients with CRC. Our data reported that upregulation of MCU enhanced the mitochondrial Ca 2+ uptake to promote mitochondrial biogenesis, which in turn facilitated CRC cell growth in vitro and in vivo. In terms of the underlying mechanism, it was identified that MCU-mediated mitochondrial Ca 2+ uptake inhibited the phosphorylation of transcription factor A, mitochondrial (TFAM), and thus enhanced its stability to promote mitochondrial biogenesis. Furthermore, our data indicated that increased mitochondrial Ca 2+ uptake led to increased mitochondrial production of ROS via the upregulation of mitochondrial biogenesis, which subsequently activated NF-κB signaling to accelerate CRC growth. In conclusion, the results indicated that MCU-induced mitochondrial Ca 2+ uptake promotes mitochondrial biogenesis by suppressing phosphorylation of TFAM, thus contributing to CRC cell growth. Our findings reveal a novel mechanism underlying mitochondrial Ca 2+-mediated CRC cell growth and may provide a potential pharmacological target for CRC treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Upregulation Of Mcu Enhances the Mitochondrial Ca 2+ Uptake mentioning

confidence: 99%

MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth

Yang

Jin

Wang

et al. 2020

Sig Transduct Target Ther

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“…The ER-mitochondrial contacts do not occur randomly, but on specific domains termed MAMs, which have a well-defined structure with several proteins present at both the OMM and the ER membrane [118]. MAMs allow a better transport of Ca 2+ to mitochondria and regulate spikes of activity through Ca 2+ transport from the ER to the mitochondria [119].The alteration of MAMs yields to the lack of Ca 2+ homeostasis and mitochondrial biogenesis impairment [97,116,120,121].…”

Section: The Role Of the Mamsmentioning

confidence: 99%

Mitostasis, Calcium and Free Radicals in Health, Aging and Neurodegeneration

et al. 2021

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Mitochondria play key roles in ATP supply, calcium homeostasis, redox balance control and apoptosis, which in neurons are fundamental for neurotransmission and to allow synaptic plasticity. Their functional integrity is maintained by mitostasis, a process that involves mitochondrial transport, anchoring, fusion and fission processes regulated by different signaling pathways but mainly by the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α also favors Ca2+ homeostasis, reduces oxidative stress, modulates inflammatory processes and mobilizes mitochondria to where they are needed. To achieve their functions, mitochondria are tightly connected to the endoplasmic reticulum (ER) through specialized structures of the ER termed mitochondria-associated membranes (MAMs), which facilitate the communication between these two organelles mainly to aim Ca2+ buffering. Alterations in mitochondrial activity enhance reactive oxygen species (ROS) production, disturbing the physiological metabolism and causing cell damage. Furthermore, cytosolic Ca2+ overload results in an increase in mitochondrial Ca2+, resulting in mitochondrial dysfunction and the induction of mitochondrial permeability transition pore (mPTP) opening, leading to mitochondrial swelling and cell death through apoptosis as demonstrated in several neuropathologies. In summary, mitochondrial homeostasis is critical to maintain neuronal function; in fact, their regulation aims to improve neuronal viability and to protect against aging and neurodegenerative diseases.

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“…Interestingly, higher ETHE1 expression lowered cellular H2S concentrations (measured by lower glutathione persulfide levels), resulting in increased phosphodiesterase activity (PDE), and adenosine monophosphate-activated protein kinase (AMPKp), sirtuin1 (SIRT1), and peroxisome proliferation-activated receptor γ-coactivator-1α activation (PGC1α, 18). In a murine xenograft model, high ETHE1 expression also accelerated colon cancer cell line growth, with increased Ki-67 and CD31 expression, reflecting increased cell growth with concomitant intensified tumor angiogenesis (18). Conversely, a comparison of twenty colonic adenocarcinomas to patient-matched benign tissues revealed lower ETHE1 mRNA and protein expression in malignant tissues compared to benign (19).…”

Section: Discussionmentioning

confidence: 89%

Ethylmalonic Encephalopathy 1 Protein Is Increased in Colorectal Adenocarcinoma

et al. 2021

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Background/Aim: Ethylmalonic encephalopathy 1 protein (ETHE1) plays an important role in sulfide catabolism and polysulfide formation. As sulfides and polysulfides have recently been identified as playing important roles in cancer, we hypothesized that ETHE1 expression would be increased in colon cancer. Materials and Methods: We used tissue microarray analysis to compare ETHE1 expression in benign colonic epithelium compared to colonic adenocarcinoma. In total, 26 benign colonic epithelial samples were compared to 122 cases of colonic adenocarcinomas. Results: Compared to benign colonic epithelium, ETHE1 expression was significantly increased (~two-fold) in colonic adenocarcinoma. Additionally, this expression increased with increasing colon cancer tumor grades. Conclusion: ETHE1 expression is increased in colon cancer compared to benign colonic epithelium. These data, combined with previous studies, suggest that ETHE1 may contribute to colon carcinogenesis by promoting tumor cell bioenergetics and polysulfide formation.Ethylmalonic encephalopathy 1 protein (ETHE1), also known as sulfur dioxygenase, is located on chromosome 19q13 and encodes a mettallo β-lactamase family enzyme containing a mononuclear iron center (1-4). Loss-of-function ETHE1 mutations are associated with ethylmalonic encephalopathy, a rare infantile autosomal recessive metabolic disorder affecting the brain, gastrointestinal tract, and peripheral vessels, characterized by psychomotor regression with generalized hypotonia, evolving into tetraparesis, dystonia, and subsequent global neurological failure and death in the first decade (3-5). Patients with ethylmalonic encephalopathy exhibit lactic acidemia, elevated urine ethylmalonic and methylsuccinic acids, and low skeletal muscle mitochondrial respiratory complex IV activity (3-5).ETHE1 functions in the mitochondrial matrix oxidizing sulfides to sulfate or sulfate esters, and taurine, through the sequential actions of sulfide: quinone oxidoreductase, ETHE1, and rhodanese (6). Specifically, ETHE1 detoxifies/oxidizes hydrogen sulfide (H2S) and glutathione polysulfides (glutathione-persulfide, -trisulfide, and -tetrasulfide), but not cysteine-or homocysteine-persulfides/polysulfides (6-8). Interestingly, ETHE1 also exhibits cysteine protein polysulfidation activities. ETHE1 persulfide dioxygenase and polysulfidation activities are dependent on Cys247 polysulfidation and replacement of the Cys247 with serine ablates both enzymatic activities (8). The enzymes that synthesize H2S, cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST), also function in polysulfide synthesis; suggesting that these enzymes and ETHE1 function together to regulate cellular polysulfide levels (8-10).Recently, one or more of the enzymes that synthesize H2S have been found to be increased in many different human malignancies, with one study of oral squamous cell carcinoma also showing significantly increased tumor H2S levels (11-13). Additionally, there is recent evide...

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ETHE1 overexpression promotes SIRT1 and PGC1α mediated aerobic glycolysis, oxidative phosphorylation, mitochondrial biogenesis and colorectal cancer

Cited by 19 publications

References 59 publications

MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth

MCU-induced mitochondrial calcium uptake promotes mitochondrial biogenesis and colorectal cancer growth

Mitostasis, Calcium and Free Radicals in Health, Aging and Neurodegeneration

Ethylmalonic Encephalopathy 1 Protein Is Increased in Colorectal Adenocarcinoma

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