Molecular Regulation Mechanisms and Interactions Between Reactive Oxygen Species and Mitophagy

Fan, Ping; Xie, Xing-Hui; Chen, Changhong; Peng, Xin; Zhang, Po; Yang, Cheng; Wang, Yuntao

doi:10.1089/dna.2018.4348

Cited by 80 publications

(54 citation statements)

References 134 publications

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“…However, NCLX knockout resulted in the selection of clones that initiate pro-survival and pro-metastatic adaptations. Mitochondrial depolarization and mtROS production are known initiators of mitophagy ( Ashrafi and Schwarz, 2013 ; Fan et al, 2019 ; Frank et al, 2012 ; Schofield and Schafer, 2020 ; Twig and Shirihai, 2011 ). Moreover, HIF1α, which is regulated in a mtCa 2+ /mtROS-dependent manner in response to NCLX loss in CRC, also contributes to mitophagy, by upregulating the pro-mitophagy proteins BNIP3 and NIX ( Bellot et al, 2009 ; Chourasia et al, 2015 ; Zhang et al, 2008 ; Zhang and Ney, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis

Pathak

Guéguinou

Walter

et al. 2020

eLife

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Despite the established role of mitochondria in cancer, the mechanisms by which mitochondrial Ca2+ (mtCa2+) regulates tumorigenesis remain incompletely understood. The crucial role of mtCa2+ in tumorigenesis is highlighted by altered expression of proteins mediating mtCa2+ uptake and extrusion in cancer. Here, we demonstrate decreased expression of the mitochondrial Na+/Ca2+/Li+ exchanger NCLX (SLC8B1) in human colorectal tumors and its association with advanced-stage disease in patients. Downregulation of NCLX causes mtCa2+ overload, mitochondrial depolarization, decreased expression of cell-cycle genes and reduced tumor size in xenograft and spontaneous colorectal cancer mouse models. Concomitantly, NCLX downregulation drives metastatic spread, chemoresistance, and expression of epithelial-to-mesenchymal, hypoxia, and stem cell pathways. Mechanistically, mtCa2+ overload leads to increased mitochondrial reactive oxygen species, which activate HIF1α signaling supporting metastasis of NCLX-null tumor cells. Thus, loss of NCLX is a novel driver of metastasis, indicating that regulation of mtCa2+ is a novel therapeutic approach in metastatic colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis

Pathak

Guéguinou

Walter

et al. 2020

eLife

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“…In addition, in hPDLSCs-MOR SOD1 is downregulated. It encodes for a protein of the superoxide dismutase family and its downregulation correlates with the reduction of the oxidative stress [78]. The immunofluorescence analysis also shows a downregulation for SOD1.…”

Section: Discussionmentioning

confidence: 99%

Moringin Pretreatment Inhibits the Expression of Genes Involved in Mitophagy in the Stem Cell of the Human Periodontal Ligament

et al. 2019

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Moringin [4-(α-L-rhamnosyloxy) benzyl isothiocyanate] is an isothiocyanate extracted from Moringa oleifera seeds. It is an antioxidant known for several biological properties useful in the treatment of neurodegenerative diseases. Several neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases are linked to dysfunctional mitochondria due to the resulting increase of Reactive Oxygen Species (ROS). Stem cell-based therapeutic treatments in neurodegenerative diseases provide an alternative strategy aimed to replace the impaired tissue. In this study were investigated the deregulated genes involved in mitophagy in the human periodontal ligament stem cells pretreated with moringin. The RNA-seq study reveals the downregulation of PINK1, with a fold change (FC) of −0.56, such as the genes involved in the phagophore formation (MAP1LC3B FC: −0.73, GABARAP FC: −0.52, GABARAPL1 FC: −0.70, GABARAPL2 FC: −0.39). The moringin pretreatment downregulates the pro−apoptotic gene BAX (−0.66) and upregulates the anti-apoptotic genes BCL2L12 (FC: 1.35) and MCL1 (FC: 0.36). The downregulation of the most of the caspases (CASP1 FC: −1.43, CASP4 FC: −0.18, CASP6 FC: −1.34, CASP7 FC: −0.46, CASP8 FC: −0.65) implies the inactivation of the apoptotic process. Our results suggest that mitochondrial dysfunctions induced by oxidative stress can be inhibited by moringin pretreatment in human periodontal ligament stem cells (hPDLSCs).

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“…However, NCLX knock-out resulted in the selection of clones that initiate pro-survival and prometastatic adaptations. Mitochondrial depolarization and mtROS production are known initiators of mitophagy (Ashrafi and Schwarz, 2013;Fan et al, 2019;Frank et al, 2012;Schofield and Schafer, 2020;Twig and Shirihai, 2011). Moreover, HIF1α, which is regulated in a mtCa 2+ /mtROS-dependent manner in response to NCLX loss in CRC (Figure 7K, L), also contributes to mitophagy, by upregulating the pro-mitophagy proteins BNIP3 and NIX (Bellot et al, 2009;Chourasia et al, 2015;Zhang et al, 2008;Zhang and Ney, 2009).…”

Section: Discussionmentioning

confidence: 99%

Colorectal adenocarcinomas downregulate the mitochondrial Na⁺/Ca²⁺exchanger NCLX to drive metastatic spread

Pathak

Guéguinou

Walter

et al. 2020

Preprint

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Highlights• The expression of NCLX is decreased in colorectal tumors and is associated with advanced-stage disease in patients. • NCLX plays a dichotomous role in colorectal tumor growth and metastasis.• NCLX downregulation causes mitophagy and reduced colorectal cancer tumor growth.• NCLX downregulation induces stemness, chemoresistance and metastasis through mtCa 2+ /ROS/HIF1α signaling axis. Graphical Abstract SummaryDespite the established role of mitochondria in tumorigenesis, the molecular mechanisms by which mitochondrial Ca 2+ (mtCa 2+ ) signaling regulates tumor growth and metastasis remain unknown. The crucial role of mtCa 2+ in tumorigenesis is highlighted by the altered expression of proteins mediating mtCa 2+ uptake and extrusion in cancer cells. Here, we demonstrate that expression of the mitochondrial Na + /Ca 2+ exchanger NCLX (SLC8B1) is decreased in colorectal tumors and is associated with advanced-stage disease in patients. We reveal that downregulation of NCLX leads to mtCa 2+ overload, mitochondrial depolarization, mitophagy, and reduced tumor size. Concomitantly, NCLX downregulation drives metastatic spread, chemoresistance, the expression of epithelial-to-mesenchymal transition (EMT), hypoxia, and stem cell pathways. Mechanistically, mtCa 2+ overload leads to an increase in mitochondrial reactive oxygen species (mtROS) which activates HIF1α signaling supporting the metastatic behavior of tumor cells lacking NCLX. Our results reveal that loss of NCLX expression is a novel driver of metastatic progression, indicating that control of mtCa 2+ levels is a novel therapeutic approach in metastatic colorectal cancer. SignificanceMitochondrial Ca 2+ (mtCa 2+ ) homeostasis is essential for cellular metabolism and growth and plays a critical role in cancer progression. mtCa 2+ uptake is mediated by an inner membrane protein complex containing the mitochondrial Ca 2+ uniporter (MCU). mtCa 2+ uptake by the MCU is followed by a ∼100-fold slower mtCa 2+ extrusion mediated by the inner mitochondrial membrane ion transporter, the mitochondrial Na + /Ca 2+ exchanger NCLX. Because NCLX is a slower transporter than the MCU, it is a crucial rate-limiting factor of mtCa 2+ homeostasis that cannot easily be compensated by another Ca 2+ transport mechanism. This represents the first study investigating the role of NCLX in tumorigenesis and metastasis. We demonstrate for the first time that colorectal cancers exhibit loss of NCLX expression and that this is associated with advancedstage disease. Intriguingly, decreased NCLX function has a dichotomous role in colorectal cancer. Thus, we reveal that NCLX loss leads to reduced primary tumor growth and overall tumor burden in vivo. Yet, the consequential increases in mtCa 2+ elicit pro-survival, hypoxic and gene transcription pathways that enhance metastatic progression. This dichotomy is a well-established feature of chemoresistant and recurrent tumor cells including cancer stem cells. Moreover, the downstream changes elicited by NCLX loss are reminiscent of mesenchym...

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Molecular Regulation Mechanisms and Interactions Between Reactive Oxygen Species and Mitophagy

Cited by 80 publications

References 134 publications

Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis

Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis

Moringin Pretreatment Inhibits the Expression of Genes Involved in Mitophagy in the Stem Cell of the Human Periodontal Ligament

Colorectal adenocarcinomas downregulate the mitochondrial Na⁺/Ca²⁺exchanger NCLX to drive metastatic spread

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Molecular Regulation Mechanisms and Interactions Between Reactive Oxygen Species and Mitophagy

Cited by 80 publications

References 134 publications

Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis

Dichotomous role of the human mitochondrial Na+/Ca2+/Li+ exchanger NCLX in colorectal cancer growth and metastasis

Moringin Pretreatment Inhibits the Expression of Genes Involved in Mitophagy in the Stem Cell of the Human Periodontal Ligament

Colorectal adenocarcinomas downregulate the mitochondrial Na+/Ca2+exchanger NCLX to drive metastatic spread

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Colorectal adenocarcinomas downregulate the mitochondrial Na⁺/Ca²⁺exchanger NCLX to drive metastatic spread