Na+ controls hypoxic signalling by the mitochondrial respiratory chain

Hernansanz-Agustín, Pablo; Choya-Foces, Carmen; Enrı́quez, José Antonio; Martínez‐Ruiz, Antonio

doi:10.1016/j.freeradbiomed.2020.12.294

Cited by 14 publications

(16 citation statements)

References 2 publications

(3 reference statements)

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“…Mitochondria-associated oxidative phosphorylation (OXPHOS) accounts for the predominant expense of oxygen [22][23][24]. Interruption on this loop can potentially suppress O 2 metabolism [25][26][27][28].…”

Section: Read Full License Introductionmentioning

confidence: 99%

Mitochondria-Targeted Nanoplatforms For Enhanced Photodynamic Therapy Against Hypoxia Tumor

Wen

Luo

Gao

et al. 2021

Preprint

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Background: Photodynamic therapy (PDT) is a promising therapeutic modality that can convert oxygen into cytotoxic reactive oxygen species (ROS) via photosensitizers to halt tumor growth. However, hypoxia and the unsatisfactory accumulation of photosensitizers in tumors severely diminish the therapeutic effect of PDT. In this study, a multistage nanoplatform is demonstrated to overcome these limitations by encapsulating photosensitizer IR780 and oxygen regulator 3-bromopyruvate (3BP) in poly (lactic-co-glycolic acid) (PLGA) nanocarriers.Results: The as-synthesized nanoplatforms penetrated deeply into the interior regions of tumors and preferentially remained in mitochondria due to the intrinsic characteristics of IR780. Meanwhile, 3BP could efficiently suppress oxygen consumption of tumor cells by inhibiting mitochondrial respiratory chain to further improve the generation of ROS. Furthermore, 3BP could abolish the excessive glycolytic capacity of tumor cells and lead to the collapse of ATP production, rendering tumor cells more susceptible to PDT. Successful tumor inhibition in animal models confirmed the therapeutic precision and efficiency. In addition, these nanoplatforms could act as fluorescence (FL) and photoacoustic (PA) imaging contrast agents, effectuating imaging-guided cancer treatment.Conclusions: This study provides an ideal strategy for cancer therapy by concurrent oxygen consumption reduction, oxygen-augmented PDT, energy supply reduction, mitochondria-targeted/deep-penetrated nanoplatforms and PA/FL dual-modal imaging guidance/monitoring. It is expected that such strategy will provide a promising alternative to maximize the performance of PDT in preclinical/clinical cancer treatment.

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Section: Read Full License Introductionmentioning

confidence: 99%

Mitochondria-Targeted Nanoplatforms For Enhanced Photodynamic Therapy Against Hypoxia Tumor

Wen

Luo

Gao

et al. 2021

Preprint

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“…, xanthine oxidase (Nomura et al, 2014;Al-Shehri et al, 2020), peroxisomes (Lismont et al, 2015;Fransen et al, 2017;Shai et al, 2018) and cytochrome P450 oxidases (Omura and Sato, 1962;Zhang et al, 2020) can be responsible for cellular ROS production and it highly depends on the stimulus and the cell type whether a single or multiple ROS sources are activated, for how long this occurs and for what purpose (Banfi et al, 2004;Gavazzi et al, 2006;Bedard and Krause, 2007;Aguirre and Lambeth, 2010;Brand, 2010;Dikalova et al, 2010;Donko et al, 2010;Carnesecchi et al, 2011;Al-Mehdi et al, 2012;Lanciano et al, 2013;Kim et al, 2014;Lambeth and Neish, 2014;Ives et al, 2015;Xu et al, 2017;Herb et al, 2019b;Hernansanz-Agustin et al, 2020;Herb and Schramm, 2021).…”

mentioning

confidence: 99%

“…However, since the ETC complexes show compartment-specific differences concerning ROS production (Fridovich, 1997;Murphy, 2009;Brand, 2010;West et al, 2011b;Herb and Schramm, 2021), this probe can only be used to measure ROS production inside mitochondria and, therefore, other cellular compartments should always be analyzed in addition. In healthy, undamaged mitochondria, ROS cannot escape the mitochondrial matrix because of the very effective antioxidative defense system (Roca and Ramakrishnan, 2013;Briston et al, 2017;Hos et al, 2017;Hernansanz-Agustin et al, 2020;Lin et al, 2020;Wang et al, 2020;Zhao et al, 2020). Only after prolonged overproduction or when the structure of the mitochondrial membranes is ruptured, either by opening of the mitochondrial permeability transition pore or direct damage, e.g., by pathogenic toxins, ROS can escape from the matrix into the cytosol (Koterski et al, 2005;Stavru et al, 2011;Roca and Ramakrishnan, 2013;Briston et al, 2017;Hos et al, 2017;Zhang Y. et al, 2019;Zhao et al, 2020).…”

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confidence: 99%

Reactive Oxygen Species: Not Omnipresent but Important in Many Locations

Herb

Gluschko

Schramm

2021

Front. Cell Dev. Biol.

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Reactive oxygen species (ROS), such as the superoxide anion or hydrogen peroxide, have been established over decades of research as, on the one hand, important and versatile molecules involved in a plethora of homeostatic processes and, on the other hand, as inducers of damage, pathologies and diseases. Which effects ROS induce, strongly depends on the cell type and the source, amount, duration and location of ROS production. Similar to cellular pH and calcium levels, which are both strictly regulated and only altered by the cell when necessary, the redox balance of the cell is also tightly regulated, not only on the level of the whole cell but in every cellular compartment. However, a still widespread view present in the scientific community is that the location of ROS production is of no major importance and that ROS randomly diffuse from their cellular source of production throughout the whole cell and hit their redox-sensitive targets when passing by. Yet, evidence is growing that cells regulate ROS production and therefore their redox balance by strictly controlling ROS source activation as well as localization, amount and duration of ROS production. Hopefully, future studies in the field of redox biology will consider these factors and analyze cellular ROS more specifically in order to revise the view of ROS as freely flowing through the cell.

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“…This has important implications for aberrant glycolytic metabolism linked with invasive behaviour 75 , given that plasma membrane cation pumps are largely fuelled by glycolytic ATP 76,77,78 . Similarly, mitochondrial Na + /Li 3+ /Ca 2+ exchanger activation by elevated [Na + ] i (K m ~12 mM) 79 would be expected to alter mitochondrial function and bioenergetics 80,81 . Processes altered by elevated [Na + ] i could therefore represent novel therapeutic loci.…”

Section: Discussionmentioning

confidence: 99%

Sodium accumulation in breast cancer predicts malignancy and treatment response

James

Leslie

et al. 2021

Preprint

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Breast cancer is the leading cause of cancer-related death in women worldwide. Development of novel noninvasive diagnostic and predictive pathophysiological biomarkers would represent a significant clinical improvement. Here, we explored the utility of non-invasive 23Na MRI to profile tumour physiology using preclinical mouse models of breast cancer. We establish that tissue Na+ concentration ([Na+]) is elevated vs non-tumour regions across multiple different tumour models. Ex vivo SBFI fluorescence imaging corroborated that this elevation in tumour [Na+] is due to increased intracellular [Na+]. Effective treatment with cytotoxic chemotherapy reduced tumour tissue [Na+], but was not detected by 1H diffusion-weighted imaging (DWI). Moreover, combining 23Na MRI and DWI measurements enabled superior classification accuracy of tumour vs non-tumour regions compared to either parameter alone. Quantification of breast tumour tissue [Na+] using 23Na MRI thus represents a novel, accurate, non-invasive diagnostic and predictive imaging biomarker.

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Na+ controls hypoxic signalling by the mitochondrial respiratory chain

Cited by 14 publications

References 2 publications

Mitochondria-Targeted Nanoplatforms For Enhanced Photodynamic Therapy Against Hypoxia Tumor

Mitochondria-Targeted Nanoplatforms For Enhanced Photodynamic Therapy Against Hypoxia Tumor

Reactive Oxygen Species: Not Omnipresent but Important in Many Locations

Sodium accumulation in breast cancer predicts malignancy and treatment response

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