Mitochondrial Communications最新文献

The significance of mitochondrial lipid metabolism in cancer stemness, survival, and proliferation, particularly in the context of metastasis, has garnered significant attention. Warburg's hypothesis posits that cancer cells primarily rely on aerobic glycolysis for survival due to mitochondrial dysfunction. However, recent evidence has challenged this perspective, emphasizing the direct involvement of mitochondria in cancer's rapid progression. Metabolic rearrangements, a hallmark of metastatic cancer, fulfill heightened energy demands during rapid proliferation, primarily through mitochondrial oxidative phosphorylation and lipid metabolism, even under hypoxic conditions. Moreover, lipid metabolism is elevated throughout the progression of metastatic cancer to meet crucial energy needs. However, the relative importance of mitochondrial lipid metabolism and aerobic glycolysis in highly aggressive cancers remains poorly defined, and further investigation could enhance treatment outcomes in cases of metastatic progression. In this context, a comprehensive understanding of mitochondrial lipid metabolism in metastatic breast cancer patients could potentially lead to significant breakthroughs in improving therapies, especially for triple-negative breast cancer.

Phase separation is a thermodynamic process used by all living organisms since the origin of life to rapidly assemble and disassemble membraneless condensates in response to changes in exogenous and endogenous stress conditions. For ∼4.5 billion years, living organisms in the three major domains of life depended upon the high chemical potential of adenosine triphosphate (ATP) to harness nonequilibrium chemical reactions that govern the formation and suppression of membraneless organelles via phase separation. Melatonin enhances the unique chemistry of ATP in water, promoting the solubilization via the adenosine moiety effect, supporting the survival of early organisms in an anoxic environment. Eukaryotes, including dinoflagellates and plants, can produce melatonin in extreme levels under stress as compensation for inadequate ATP for optimal regulation of survival responses dependent upon phase separation. The production of ATP and melatonin in mitochondria enables the fine-tuning of dynamics that modulate phase separation of proteins associated with ATP production, biogenesis and degradation, membrane dynamics, gene transcription, mitophagy, unfolded protein response, and apoptosis/survival responses in mitochondria. Exogenous melatonin application enhances mitochondrial ATP production and synergy, attenuating aberrant phase separation and associated mitochondrial dysfunction and disease.

Kidney diseases are a growing health problem worldwide, causing millions of deaths. Acute kidney injury (AKI) commonly evolves into chronic kidney disease (CKD) and fibrosis, which is a feature of CKD predisposing to end-stage renal disease. Thus, treatments that avoid this transition are urgently necessary. Mitochondria are the hub energy house of the renal cells, which provides energy in adenosine triphosphate (ATP) form, commonly obtained from β-oxidation through fatty acids degradation into the mitochondrial matrix. Mitochondria are plastic organelles that constantly change according to the cell's energy requirements. For this, mitochondria carry out biogenesis, fission, fusion, and mitophagy/autophagy, processes highly regulated to maintain mitochondrial bioenergetics and homeostasis. Alterations in one or more of these processes might cause detrimental consequences that affect cell function. In this sense, it is widely accepted that mitochondrial dysfunction associated with oxidative stress plays a crucial role in developing kidney diseases. Therefore, antioxidants that target mitochondria might be an excellent strategy to ameliorate mitochondrial dysfunction, and selecting one or another antioxidant could depend on AKI or CKD requirements. This review focuses on potent antioxidants such as sulforaphane (SFN), N-acetyl cysteine (NAC), resveratrol, curcumin, quercetin, and α-mangostin in the improvement of mitochondrial function in kidney pathologies.

Photobleaching and phototoxicity can induce detrimental effects on cell viability and compromise the integrity of collected data, particularly in studies utilizing super-resolution microscopes. Given the involvement of multiple factors, it is currently challenging to propose a single set of standards for assessing the potential of phototoxicity. The objective of this paper is to present empirical data on the effects of photobleaching and phototoxicity on mitochondria during super-resolution imaging of mitochondrial structure and function using Airyscan and the fluorescent structure dyes Mitotracker green (MTG), 10-N-nonyl acridine orange (NAO), and voltage dye Tetramethylrhodamine, Ethyl Ester (TMRE). We discern two related phenomena. First, phototoxicity causes a transformation of mitochondria from tubular to spherical shape, accompanied by a reduction in the number of cristae. Second, phototoxicity impacts the mitochondrial membrane potential. Through these parameters, we discovered that upon illumination, NAO is much more phototoxic to mitochondria compared to MTG or TMRE and that these parameters can be used to evaluate the relative phototoxicity of various mitochondrial dye-illumination combinations during mitochondrial imaging.

Recent high-resolution pH measurements in mitochondria show ΔpH across the F₁F₀ ATP synthase to be quite low, 0.07–0.32. Our meta-analysis of published values of transmembrane potential ($\Delta \psi$) shows it to be identical in vivo and in vitro: -159 ± 16 mV. With the low ΔpH, the thermodynamic efficiency of proton-driven ATP synthesis exceeds 100 % for average- and low-potential (−123 mV) mitochondria, and possibly also for high-potential (−180 mV) mitochondria. Efficiencies exceeding 100 % may violate the second law of thermodynamics, and suggest a need for localized chemiosmosis, i.e., the existence of a membrane surface ΔpH that exceeds the bulk phase ΔpH by at least 0.2 units in high-potential mitochondria, and by 1.1 units in low-potential mitochondria. The lack of equilibration between protons in the bulk phase and those at the membrane surface is explained by two models which we discuss and compare: the potential well/barrier model, and the TELP protonic capacitor model.

Signal transducer and activator of transcription (STAT) 3 has been found within mitochondria in addition to its canonical role of shuttling between cytoplasm and nucleus during cytokine signaling. Mitochondrial STAT3 has been implicated in modulation of cellular metabolism, largely through effects on the respiratory electron transport chain. However, the structural requirements underlying mitochondrial targeting and function have remained unclear. Here, we show that mitochondrial STAT3 partitions between mitochondrial compartments defined by differential detergent solubility, suggesting that mitochondrial STAT3 is membrane associated. The majority of STAT3 was found in an SDS soluble fraction copurifying with respiratory chain proteins, including numerous components of the complex I NADH dehydrogenase, while a minor component was found with proteins of the mitochondrial translation machinery. Mitochondrial targeting of STAT3 required the amino-terminal domain, and an internal linker domain motif also directed mitochondrial translocation. However, neither the phosphorylation of serine 727 nor the presence of mitochondrial DNA was required for the mitochondrial localization of STAT3. Two cysteine residues in the STAT3 SH2 domain, which have been previously suggested to be targets for protein palmitoylation, were also not required for mitochondrial translocation, but were required for its function as an enhancer of complex I activity. These structural determinants of STAT3 mitochondrial targeting and function provide potential therapeutic targets for disrupting the activity of mitochondrial STAT3 in diseases such as cancer.

While it has been shown that Ca²⁺ dynamics at the ER membrane is essential for the initiation of certain types of autophagy such as starvation-induced autophagy, how mitochondrial Ca²⁺ transport changes during the first stage of autophagy is not systemically characterized. An investigation of mitochondrial Ca²⁺ dynamics during autophagy initiation may help us determine the relationship between autophagy and mitochondrial Ca²⁺ fluxes. Here we examine acute mitochondrial and ER calcium responses to a panel of autophagy inducers in different cell types. Mitochondrial Ca²⁺ transport and Ca²⁺ transients at the ER membrane are triggered by different autophagy inducers. The mitophagy-inducer-initiated mitochondrial Ca²⁺ uptake relies on mitochondrial calcium uniporter and may decelerate the following mitophagy. In neurons derived from a Parkinson's patient, mitophagy-inducer-triggered mitochondrial Ca²⁺ influx is faster, which may slow the ensuing mitophagy.