Non-small cell lung cancer (NSCLC) is one of the most prevalent and lethal types of cancers worldwide and its high incidence and mortality rates pose a significant public health challenge. Despite sig Show more
Non-small cell lung cancer (NSCLC) is one of the most prevalent and lethal types of cancers worldwide and its high incidence and mortality rates pose a significant public health challenge. Despite significant advances in targeted therapy and immunotherapy, the overall prognosis of patients with NSCLC remains poor. Hypoxia is a critical driving factor in tumor progression, influencing the biological behavior of tumor cells through complex molecular mechanisms. The present review systematically examined the role of the hypoxic microenvironment in NSCLC, demonstrating its crucial role in promoting tumor cell growth, invasion and metastasis. Additionally, it has been previously reported that the hypoxic microenvironment enhances tumor cell resistance by activating hypoxia-inducible factor and regulating exosome secretion. The hypoxic microenvironment also enables tumor cells to adapt to low oxygen and nutrient-deficient conditions by enhancing metabolic reprogramming, such as through upregulating glycolysis. Further studies have shown that the hypoxic microenvironment facilitates immune escape by modulating tumor-associated immune cells and suppressing the antitumor response of the immune system. Moreover, the hypoxic microenvironment increases tumor resistance to radiotherapy, chemotherapy and other types of targeted therapy through various pathways, significantly reducing the therapeutic efficacy of these treatments. Therefore, it could be suggested that early detection of cellular hypoxia and targeted therapy based on hypoxia may offer new therapeutic approaches for patients with NSCLC. The present review not only deepened the current understanding of the mechanisms of action and role of the hypoxic microenvironment in NSCLC but also provided a solid theoretical basis for the future development of precision treatments for patients with NSCLC. Show less
Mitochondria take up Ca 2+ through the mitochondrial calcium uniporter complex to regulate energy production, cytosolic Ca 2+ signaling, and cell death 1 , 2 . In mammals, the uniporter complex (u Show more
Mitochondria take up Ca 2+ through the mitochondrial calcium uniporter complex to regulate energy production, cytosolic Ca 2+ signaling, and cell death 1 , 2 . In mammals, the uniporter complex (uniplex) contains four core components: the pore-forming MCU, gatekeeper MICU1 and MICU2, and an auxiliary EMRE subunit essential for Ca 2+ transport 3 – 8 . To prevent detrimental Ca 2+ overload, the activity of MCU must be tightly regulated by MICUs, which sense the changes in cytosolic Ca 2+ concentrations to switch MCU on and off 9 , 10 . Here, we report cryo-EM structures of human mitochondrial calcium uniporter holocomplex in inhibited and Ca 2+ -activated states. These structures define the architecture of this multi-component Ca 2+ uptake machinery and reveal the gating mechanism by which MICUs control uniporter activity. This work provides a framework for understanding regulated Ca 2+ uptake in mitochondria and lends clues to modulate uniporter activity for treating mitochondrial Ca 2+ overload-related diseases. Show less
The field of mitochondrial ion channels has undergone a rapid development during the last three decades, due to the molecular identification of some of the channels residing in the outer and inner mem Show more
The field of mitochondrial ion channels has undergone a rapid development during the last three decades, due to the molecular identification of some of the channels residing in the outer and inner membranes. Relevant information about the function of these channels in physiological and pathological settings was gained thanks to genetic models for a few, mitochondria-specific channels. However, many ion channels have multiple localizations within the cell, hampering a clear-cut determination of their function by pharmacological means. The present review summarizes our current knowledge about the ins and outs of mitochondrial ion channels, with special focus on the channels that have received much attention in recent years, namely, the voltage-dependent anion channels, the permeability transition pore (also called mitochondrial megachannel), the mitochondrial calcium uniporter and some of the inner membrane-located potassium channels. In addition, possible strategies to overcome the difficulties of specifically targeting mitochondrial channels versus their counterparts active in other membranes are discussed, as well as the possibilities of modulating channel function by small peptides that compete for binding with protein interacting partners. Altogether, these promising tools along with large-scale chemical screenings set up to identify new, specific channel modulators will hopefully allow us to pinpoint the actual function of most mitochondrial ion channels in the near future and to pharmacologically affect important pathologies in which they are involved, such as neurodegeneration, ischaemic damage and cancer. LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc. Show less
Abstract Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology Show more
Abstract Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δ p or its potential component, Δ Ψ , which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1–5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling. Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δ p dissipation decreases superoxide formation dependent on Δ p . UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells. Critical Issues: A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg 2+ , or increased pyruvate accumulation may initiate UCP-mediated redox signaling. Future Directions: Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667–714. Show less
Mitochondrial calcium uptake plays critical roles in regulating ATP
production, intracellular calcium signaling, and cell death. This uptake is
mediated by a highly selective calcium channel called th Show more
Mitochondrial calcium uptake plays critical roles in regulating ATP
production, intracellular calcium signaling, and cell death. This uptake is
mediated by a highly selective calcium channel called the mitochondrial calcium
uniporter. Here, we determined the structures of the pore-forming MCU proteins
by X-ray crystallography and single-particle cryo-electron microscopy. The
stoichiometry, overall architecture, and individual subunit structure differed
markedly from those in the recent nuclear magnetic resonance structure of the
Caenorhabditis elegans MCU. In our studies, we observed a dimer-of-dimer
architecture across species and chemical environments, which was corroborated by
biochemical experiments. Structural analyses and functional characterizations
uncovered the roles of critical residues in the pore. These results reveal a new
ion channel architecture, provide insights into calcium coordination,
selectivity, and conduction, and establish a structural framework for
understanding the mechanism of mitochondrial calcium uniporter function. Show less