The Mitochondrial Complex(I)ty of Cancer

Urra, Félix A.; Muñoz, Felipe Vilo; Lovy, Alenka; Cárdenas, César

doi:10.3389/fonc.2017.00118

Cited by 126 publications

(120 citation statements)

References 105 publications

(136 reference statements)

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“…2E, F), whereas no difference on the activity of Complex Ⅱ-Ⅳ was seen (Data not shown), indicating that RPL10 is most likely to involve in the function of mitochondrial Complex I. Given the fact that Complex Ⅰ catalyzes NADH oxidation and transports protons across the inner mitochondrial membrane, leading to energy and ROS production [26], [27], [28], [29], [30] and knock-down of RPL10 could result in the changes of Complex Ⅰ and ATP, it was crucial to investigate the relationship between RPL10 and ROS level in pancreatic cancer cells.…”

Section: Resultsmentioning

confidence: 92%

Ribosomal protein L10 in mitochondria serves as a regulator for ROS level in pancreatic cancer cells

et al. 2018

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Tumorigenesis is commonly known as a complicated process, in which reactive oxygen species (ROS) plays a critical role to involve in signal transduction, metabolism, cell proliferation and differentiation. Previously, ribosomal protein L10 (RPL10) was suggested to possess extra-ribosomal functions in pancreatic cancer cells in addition to being proposed as a tumor suppressor or transcription co-regulator. To better understand the relationship between RPL10 and tumorigenic potential in pancreatic cancer cells, chromatin immunoprecipitation sequencing reveals that RPL10 is unlikely to be a transcription factor without a specific binding motif for gene transcription. Additionally, transcriptome analysis indicates that RPL10 could regulate the expression of proteins related to ROS production. Moreover, RPL10 in mitochondria is closely associated with the regulation of ROS level by affecting Complex I activity and the subsequent events. Together, the present study suggests that the regulation of ROS level by mitochondrial RPL10 is one of the major extra-ribosomal functions in pancreatic cancer cells, which could be used as an indicator for the tumorigenesis of pancreatic cancer.

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Section: Resultsmentioning

confidence: 92%

Ribosomal protein L10 in mitochondria serves as a regulator for ROS level in pancreatic cancer cells

et al. 2018

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“…Our results showed that GA-TPP + C 10 also produces mixed time-dependent inhibition of αKGDHC activity in the BC cells. Early observations regarding a direct interaction and functional dependence by measurement of the NAD + /NADH ratio between Complex I and αKGDHC [65,66], as well as the role of Complex I activity in the control of the proton-motive force for ATP-coupled respiration [42] and maintaining mitochondrial aspartate synthesis [40,41], suggest that the complex mitochondrial dysfunction induced by GA-TPP + C 10 mediated by Complex I and αKGDHC inhibition blocks an essential step required for cancer cell survival and proliferation. Recent evidence indicates that selective Complex I inhibition decreases intracellular aspartate levels by decreasing the NAD + pool, which is used as a substrate for αKGDHC for NADH regeneration in the TCA cycle, providing carbon units for DNA synthesis during proliferation [40,41].…”

Section: Discussionmentioning

confidence: 99%

“…Prolonged GA-TPP + C 10 treatment (24 h) modified the kinetic parameters of αKGDHC, decreasing the Vmax and increasing the Km at 5 and 10 µM, indicating a mixed-inhibition model, as suggested by the Michaelis-Menten modeling ( Figure 4C,D,F,G). The coordinated function of Complex I and αKGDHC is required for maintaining the mitochondrial NAD + /NADH ratio, which is essential for the synthesis of aspartate [40][41][42]. To determine whether the inhibition of Complex I and αKGDHC by GA-TPP + C 10 has implications in the anticancer effect exhibited in BC cells, we added the exogenous metabolic substrate Pyr and the cell-penetrating intermediates mAsp and dm-KG, and the viability in the presence of GA-TPP + C 10 was evaluated at 48 h of exposure.…”

Section: Prolonged Ga-tpp + C 10 Treatment Induces Mixed Inhibition Omentioning

confidence: 99%

“…To determine whether the inhibition of Complex I and αKGDHC by GA-TPP + C 10 has implications in the anticancer effect exhibited in BC cells, we added the exogenous metabolic substrate Pyr and the cell-penetrating intermediates mAsp and dm-KG, and the viability in the presence of GA-TPP + C 10 was evaluated at 48 h of exposure. Pyr addition was shown to rescue the antiproliferative effect only of ETC inhibitors [40][41][42] by lactate dehydrogenase-dependent NADH regeneration, and mAsp and dm-αKG addition rescued the carbon source for nucleotide biosynthesis and αKGDHC activity-dependent glutaminolysis [29,43,44]. As shown in Figure 4D,G, consistent with the αKGDHC activity assay, both dm-αKG and mAsp, but not Pyr, partially rescued the cytotoxic effect of GA-TPP + C 10 in the MCF7 and MDA-MB-231 cancer cells, suggesting that inhibition of αKGDHC activity is a relevant step for the promotion of mitochondrial dysfunction.…”

Section: Prolonged Ga-tpp + C 10 Treatment Induces Mixed Inhibition Omentioning

confidence: 99%

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Complex Mitochondrial Dysfunction Induced by TPP+-Gentisic Acid and Mitochondrial Translation Inhibition by Doxycycline Evokes Synergistic Lethality in Breast Cancer Cells

Fuentes-Retamal

Sandoval-Acuña

Peredo-Silva

et al. 2020

Cells

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The mitochondrion has emerged as a promising therapeutic target for novel cancer treatments because of its essential role in tumorigenesis and resistance to chemotherapy. Previously, we described a natural compound, 10-((2,5-dihydroxybenzoyl)oxy)decyl) triphenylphosphonium bromide (GA-TPP+C10), with a hydroquinone scaffold that selectively targets the mitochondria of breast cancer (BC) cells by binding to the triphenylphosphonium group as a chemical chaperone; however, the mechanism of action remains unclear. In this work, we showed that GA-TPP+C10 causes time-dependent complex inhibition of the mitochondrial bioenergetics of BC cells, characterized by (1) an initial phase of mitochondrial uptake with an uncoupling effect of oxidative phosphorylation, as previously reported, (2) inhibition of Complex I-dependent respiration, and (3) a late phase of mitochondrial accumulation with inhibition of α-ketoglutarate dehydrogenase complex (αKGDHC) activity. These events led to cell cycle arrest in the G1 phase and cell death at 24 and 48 h of exposure, and the cells were rescued by the addition of the cell-penetrating metabolic intermediates l-aspartic acid β-methyl ester (mAsp) and dimethyl α-ketoglutarate (dm-KG). In addition, this unexpected blocking of mitochondrial function triggered metabolic remodeling toward glycolysis, AMPK activation, increased expression of proliferator-activated receptor gamma coactivator 1-alpha (pgc1α) and electron transport chain (ETC) component-related genes encoded by mitochondrial DNA and downregulation of the uncoupling proteins ucp3 and ucp4, suggesting an AMPK-dependent prosurvival adaptive response in cancer cells. Consistent with this finding, we showed that inhibition of mitochondrial translation with doxycycline, a broad-spectrum antibiotic that inhibits the 28 S subunit of the mitochondrial ribosome, in the presence of GA-TPP+C10 significantly reduces the mt-CO1 and VDAC protein levels and the FCCP-stimulated maximal electron flux and promotes selective and synergistic cytotoxic effects on BC cells at 24 h of treatment. Based on our results, we propose that this combined strategy based on blockage of the adaptive response induced by mitochondrial bioenergetic inhibition may have therapeutic relevance in BC.

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“…The most prominent complexes with higher assembly levels in high-grade PCa, compared with normal prostate and low-grade PCa, are mitochondrial complex I and its subcomplexes ( Table 1). As the largest complex of the mitochondrial electron transport chain, mitochondrial complex I contributes ~40% of the proton motive force required for mitochondrial ATP synthesis [64]. Moreover, via modulating the NAD+/NADH ratio, mitochondrial complex I controls the synthesis of aspartate, a precursor of purine and pyrimidine synthesis.…”

Section: Differentially Regulated Protein Complexesmentioning

confidence: 99%

Quantitative Proteomic Analysis of Prostate Tissue Specimens Identifies Deregulated Protein Complexes in Primary Prostate Cancer

Zhou

Yan

Wang

et al. 2018

Preprint

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Prostate cancer (PCa) is the most frequently diagnosed non-skin cancer and a leading cause of mortality among males in developed countries. However, our understanding of the global changes of protein complexes within PCa tissue specimens remains very limited, although it has been well recognized that protein complexes carry out essentially all major processes in living organisms and that their deregulation drives the pathogenesis and progression of various diseases. By coupling tandem mass taggingsynchronous precursor selection-mass spectrometry/mass spectrometry/mass spectrometry (TMT-SPS-MS3) with differential expression and co-regulation analyses, the present study compared the differences between protein complexes in normal prostate, low-grade PCa, and high-grade PCa tissue specimens.Globally, a large downregulated putative protein-protein interaction (PPI) network was detected in both low-grade and high-grade PCa, yet a large upregulated putative PPI network was only detected in highgrade but not low-grade PCa, compared with normal controls. To identify specific protein complexes that are deregulated in PCa, quantified proteins were mapped to protein complexes in CORUM, a collection of experimentally verified mammalian protein complexes. Differential expression analysis suggested that mitochondrial ribosomes and the fibrillin-associated protein complex were significantly overexpressed, whereas the ITGA6-ITGB4-Laminin10/12 and the P2X7 receptor signaling complexes were significantly downregulated, in PCa compared with normal prostate. Moreover, differential co-regulation analysis indicated that the assembly levels of some nuclear protein complexes involved in RNA synthesis and processing were significantly increased in low-grade PCa, and those of mitochondrial complex I and its subcomplexes were significantly increased in high-grade PCa, compared with normal prostate. In summary, the study represents the first global and quantitative comparison of protein complexes in prostate tissue specimens. It is expected to enhance our understanding of the molecular mechanisms underlying PCa development and progression in human patients, as well as lead to the discovery of novel biomarkers and therapeutic targets for precision management of PCa.

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The Mitochondrial Complex(I)ty of Cancer

Cited by 126 publications

References 105 publications

Ribosomal protein L10 in mitochondria serves as a regulator for ROS level in pancreatic cancer cells

Ribosomal protein L10 in mitochondria serves as a regulator for ROS level in pancreatic cancer cells

Complex Mitochondrial Dysfunction Induced by TPP+-Gentisic Acid and Mitochondrial Translation Inhibition by Doxycycline Evokes Synergistic Lethality in Breast Cancer Cells

Quantitative Proteomic Analysis of Prostate Tissue Specimens Identifies Deregulated Protein Complexes in Primary Prostate Cancer

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