-
Anti-cancer Agents in Medicinal... 2017It is a longstanding debate whether cancer is one disease or a set of very diverse diseases. The goal of this paper is to suggest strongly that most of (if not all) the... (Review)
Review
It is a longstanding debate whether cancer is one disease or a set of very diverse diseases. The goal of this paper is to suggest strongly that most of (if not all) the hallmarks of cancer could be the consequence of the Warburg's effect. As a result of the metabolic impairment of the oxidative phosphorylation, there is a decrease in ATP concentration. To compensate the reduced energy yield, there is massive glucose uptake, anaerobic glycolysis, with an up-regulation of the Pentose Phosphate Pathway resulting in increased biosynthesis leading to increased cell division and local pressure. This increased pressure is responsible for the fractal shape of the tumor, the secretion of collagen by the fibroblasts and plays a critical role in metastatic spread. The massive extrusion of lactic acid contributes to the extracellular acidity and the activation of the immune system. The decreased oxidative phosphorylation leads to impairment in CO2 levels inside and outside the cell, with increased intracellular alkalosis and contribution of carbonic acid to extracellular acidosis-mediated by at least two cancer-associated carbonic anhydrase isoforms. The increased intracellular alkalosis is a strong mitogenic signal, which bypasses most inhibitory signals. Mitochondrial disappearance (such as seen in very aggressive tumors) is a consequence of mitochondrial swelling, itself a result of decreased ATP concentration. The transmembrane pumps, which extrude, from the mitochondria, ions, and water, are ATP-dependant. Therapy aiming at increasing both the number and the efficacy of mitochondria could be very useful.
Topics: Acidosis; Adenosine Triphosphate; Alkalosis; Animals; Carbon Dioxide; Cell Proliferation; Citrates; Glucose; Glycolysis; Humans; Mitochondria; Neoplasms; Oxidative Phosphorylation; Pentose Phosphate Pathway; Thioctic Acid
PubMed: 27804847
DOI: 10.2174/1871520616666161031143301 -
Hepatology (Baltimore, Md.) Jan 2023Increased megamitochondria formation and impaired mitophagy in hepatocytes have been linked to the pathogenesis of alcohol-associated liver disease (ALD). This study...
BACKGROUND AND AIMS
Increased megamitochondria formation and impaired mitophagy in hepatocytes have been linked to the pathogenesis of alcohol-associated liver disease (ALD). This study aims to determine the mechanisms by which alcohol consumption increases megamitochondria formation in the pathogenesis of ALD.
APPROACH AND RESULTS
Human alcoholic hepatitis (AH) liver samples were used for electron microscopy, histology, and biochemical analysis. Liver-specific dynamin-related protein 1 (DRP1; gene name DNM1L, an essential gene regulating mitochondria fission ) knockout (L-DRP1 KO) mice and wild-type mice were subjected to chronic plus binge alcohol feeding. Both human AH and alcohol-fed mice had decreased hepatic DRP1 with increased accumulation of hepatic megamitochondria. Mechanistic studies revealed that alcohol feeding decreased DRP1 by impairing transcription factor EB-mediated induction of DNM1L . L-DRP1 KO mice had increased megamitochondria and decreased mitophagy with increased liver injury and inflammation, which were further exacerbated by alcohol feeding. Seahorse flux and unbiased metabolomics analysis showed alcohol intake increased mitochondria oxygen consumption and hepatic nicotinamide adenine dinucleotide (NAD + ), acylcarnitine, and ketone levels, which were attenuated in L-DRP1 KO mice, suggesting that loss of hepatic DRP1 leads to maladaptation to alcohol-induced metabolic stress. RNA-sequencing and real-time quantitative PCR analysis revealed increased gene expression of the cGAS-stimulator of interferon genes (STING)-interferon pathway in L-DRP1 KO mice regardless of alcohol feeding. Alcohol-fed L-DRP1 KO mice had increased cytosolic mtDNA and mitochondrial dysfunction leading to increased activation of cGAS-STING-interferon signaling pathways and liver injury.
CONCLUSION
Alcohol consumption decreases hepatic DRP1 resulting in increased megamitochondria and mitochondrial maladaptation that promotes AH by mitochondria-mediated inflammation and cell injury.
Topics: Mice; Humans; Animals; Hepatitis, Alcoholic; Mitochondrial Swelling; Liver Diseases, Alcoholic; Mitochondria; Ethanol; Nucleotidyltransferases; Inflammation; Interferons; Mitochondrial Dynamics
PubMed: 35698731
DOI: 10.1002/hep.32604 -
Cardiovascular Diabetology Jan 2021Sodium-glucose linked transporter type 2 (SGLT-2) inhibition has been shown to reduce cardiovascular mortality in heart failure independently of glycemic control and...
BACKGROUND
Sodium-glucose linked transporter type 2 (SGLT-2) inhibition has been shown to reduce cardiovascular mortality in heart failure independently of glycemic control and prevents the onset of atrial arrhythmias, a common co-morbidity in heart failure with preserved ejection fraction (HFpEF). The mechanism behind these effects is not fully understood, and it remains unclear if they could be further enhanced by additional SGLT-1 inhibition. We investigated the effects of chronic treatment with the dual SGLT-1&2 inhibitor sotagliflozin on left atrial (LA) remodeling and cellular arrhythmogenesis (i.e. atrial cardiomyopathy) in a metabolic syndrome-related rat model of HFpEF.
METHODS
17 week-old ZSF-1 obese rats, a metabolic syndrome-related model of HFpEF, and wild type rats (Wistar Kyoto), were fed 30 mg/kg/d sotagliflozin for 6 weeks. At 23 weeks, LA were imaged in-vivo by echocardiography. In-vitro, Ca transients (CaT; electrically stimulated, caffeine-induced) and spontaneous Ca release were recorded by ratiometric microscopy using Ca-sensitive fluorescent dyes (Fura-2) during various experimental protocols. Mitochondrial structure (dye: Mitotracker), Ca buffer capacity (dye: Rhod-2), mitochondrial depolarization (dye: TMRE) and production of reactive oxygen species (dye: H2DCF) were visualized by confocal microscopy. Statistical analysis was performed with 2-way analysis of variance followed by post-hoc Bonferroni and student's t-test, as applicable.
RESULTS
Sotagliflozin ameliorated LA enlargement in HFpEF in-vivo. In-vitro, LA cardiomyocytes in HFpEF showed an increased incidence and amplitude of arrhythmic spontaneous Ca release events (SCaEs). Sotagliflozin significantly reduced the magnitude of SCaEs, while their frequency was unaffected. Sotagliflozin lowered diastolic [Ca] of CaT at baseline and in response to glucose influx, possibly related to a ~ 50% increase of sodium sodium-calcium exchanger (NCX) forward-mode activity. Sotagliflozin prevented mitochondrial swelling and enhanced mitochondrial Ca buffer capacity in HFpEF. Sotagliflozin improved mitochondrial fission and reactive oxygen species (ROS) production during glucose starvation and averted Ca accumulation upon glycolytic inhibition.
CONCLUSION
The SGLT-1&2 inhibitor sotagliflozin ameliorated LA remodeling in metabolic HFpEF. It also improved distinct features of Ca-mediated cellular arrhythmogenesis in-vitro (i.e. magnitude of SCaEs, mitochondrial Ca buffer capacity, diastolic Ca accumulation, NCX activity). The safety and efficacy of combined SGLT-1&2 inhibition for the treatment and/or prevention of atrial cardiomyopathy associated arrhythmias should be further evaluated in clinical trials.
Topics: Animals; Arrhythmias, Cardiac; Atrial Function, Left; Atrial Remodeling; Calcium Signaling; Disease Models, Animal; Glycosides; Heart Atria; Heart Failure; Metabolic Syndrome; Mitochondria, Heart; Mitochondrial Dynamics; Mitochondrial Swelling; Rats, Inbred WKY; Rats, Zucker; Reactive Oxygen Species; Sodium-Calcium Exchanger; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Rats
PubMed: 33413413
DOI: 10.1186/s12933-020-01208-z -
International Journal of Biological... 2022Triple-negative breast cancer (TNBC) is a massive threat to women's health due to its high morbidity, malignancy, and the refractory, effective therapeutic option of...
Triple-negative breast cancer (TNBC) is a massive threat to women's health due to its high morbidity, malignancy, and the refractory, effective therapeutic option of TNBC is still deficient. The mitochondrial protein showed therapeutic potential on breast cancer, whereas the mechanism and downstream pathway of mitochondrial uncoupling protein 1 (UCP1) was not fully elucidated. We found that UCP1 was negatively regulated to the process of TNBC. Overexpressing UCP1 could inhibit the proliferation and metastasis of TNBC, meanwhile inducing the mitochondrial swelling and activation of mitophagy . Mitophagy activation was then assessed to elucidate whether it was downstream of UCP1 in TNBC metastasis. GSDME is the core of pyroptosis. We found that GSDME was activated in the TNBC cells when UCP1 levels were high. It regulates TNBC cell proliferation potential instead of the apoptosis process and . Our results suggested that UCP1 could inhibit the process of TNBC by activating mitophagy and pyroptosis. Impaired activation of mitophagy weakens the regulation effect of UCP1 on metastasis of TNBC, similar to the impairment of GSDME activation on the proliferation regulation of UCP1 on TNBC. UCP1 might be a novel therapeutic target of TNBC.
Topics: Cell Line, Tumor; Cell Proliferation; Female; Humans; Mitochondrial Proteins; Mitophagy; Pyroptosis; Triple Negative Breast Neoplasms; Uncoupling Protein 1
PubMed: 35541900
DOI: 10.7150/ijbs.68438 -
BioRxiv : the Preprint Server For... Feb 2023Right ventricular dysfunction (RVD) is a risk factor for mortality in multiple cardiovascular diseases, but approaches to combat RVD are lacking. Therapies used for left...
Right ventricular dysfunction (RVD) is a risk factor for mortality in multiple cardiovascular diseases, but approaches to combat RVD are lacking. Therapies used for left heart failure are largely ineffective in RVD, and thus the identification of molecules that augment RV function could improve outcomes in a wide-array of cardiac limitations. Junctophilin-2 (JPH2) is an essential protein that plays important roles in cardiomyocytes, including calcium handling/maintenance of t-tubule structure and gene transcription. Additionally, JPH2 may regulate mitochondrial function as knockout mice exhibit cardiomyocyte mitochondrial swelling and cristae derangements. Moreover, JPH2 knockdown in embryonic stem cell-derived cardiomyocytes induces downregulation of the mitochondrial protein mitofusin-2 (MFN2), which disrupts mitochondrial cristae structure and transmembrane potential. Impaired mitochondrial metabolism drives RVD, and here we evaluated the mitochondrial role of JPH2. We showed JPH2 directly interacts with MFN2, ablation of JPH2 suppresses mitochondrial biogenesis, oxidative capacity, and impairs lipid handling in iPSC-CM. Gene therapy with AAV9-JPH2 corrects RV mitochondrial morphological defects, mitochondrial fatty acid metabolism enzyme regulation, and restores the RV lipidomic signature in the monocrotaline rat model of RVD. Finally, AAV-JPH2 improves RV function without altering PAH severity, showing JPH2 provides an inotropic effect to the dysfunction RV.
PubMed: 36798293
DOI: 10.1101/2023.02.07.527576 -
Biophysical Chemistry Nov 2021Mitochondrial activity as regards ATP production strongly depends on mitochondrial swelling (MS) mode. Therefore, this work analyzes reversible and irreversible MS using...
Mitochondrial activity as regards ATP production strongly depends on mitochondrial swelling (MS) mode. Therefore, this work analyzes reversible and irreversible MS using a detailed biophysical model. The reported model includes mechanical properties of the inner mitochondrial membrane (IMM). The model describes MS dynamics for spherically symmetric, axisymmetric ellipsoidal and general ellipsoidal mitochondria. Mechanical stretching properties of the IMM were described by a second-rank rigidity tensor. The tensor components were estimated by fitting to the earlier reported results of in vitro experiments. The IMM rigidity constant of ca. 0.008 dyn/nm was obtained for linear deformations. The model also included membrane bending effects, which were small compared to those of membrane stretching. The model was also tested by simulation of the earlier reported experimental data and of the system dynamics at different initial conditions, predicting the system behavior. The transition criteria from reversible to irreversible swelling were determined and tested. The presently developed model is applicable directly to the analysis of in vitro experimental data, while additional improvements are necessary before it could be used to describe mitochondrial swelling in vivo. The reported theoretical model also provides an idea of physically consistent mechanism for the permeability transport pore (PTP) opening, which depends on the IMM stretching stress. In the current study, this idea is discussed briefly, but a detailed theoretical analysis of these ideas will be performed later. The currently developed model provides new understanding of the detailed MS mechanism and of the conditions for the transition between reversible and irreversible MS modes. On the other hand, the current model provides useful mathematical tools, that may be successfully used in mitochondrial biophysics research, and also in other applications, predicting the behavior of mitochondria in different conditions of the surrounding media in vitro or cellular cyto(sarco)plasm in vivo. These mathematical tools are based on real biophysical processes occurring in mitochondria. Thus, we note a significant progress in the theoretical approach, which may be used in real biological systems, compared to the earlier reported models. Significance of this study derives from inclusion of IMM mechanical properties, which directly impact the reversible and irreversible mitochondrial swelling dynamics. Reversible swelling corresponds to reversible IMM deformations, while irreversible swelling corresponds to irreversible deformations, with eventual membrane disruption. The IMM mechanical properties are directly dependent on the membrane biochemical composition and structure. The IMM deformationas are induced by osmotic pressure created by the ionic/neutral solute imbalance between the mitochondrial matrix media and the bulk solution in vitro, or cyto(sarco)plasm in vivo. The novelty of the reported model is in the biophysical mechanism detailing ionic and neutral solute transport for a large number of solutes, which were not taken into account in the earlier reported biophysical models of MS. Therefore, the reported model allows understanding response of mitochondria to the changes of initial concentration(s) of any of the solute(s) included in the model. Note that the values of all of the model parameters and kinetic constants have been estimated and the resulting complete model may be used for quantitative analysis of mitochondrial swelling dynamics in conditions of real in vitro experiments.
Topics: Biophysical Phenomena; Calcium; Computer Simulation; Mitochondria; Mitochondrial Membranes; Mitochondrial Swelling
PubMed: 34418677
DOI: 10.1016/j.bpc.2021.106668 -
Liver International : Official Journal... Nov 2023This thematic review aims to provide an overview of the current state of knowledge about the occurrence of giant mitochondria or megamitochondria in liver parenchymal... (Review)
Review
This thematic review aims to provide an overview of the current state of knowledge about the occurrence of giant mitochondria or megamitochondria in liver parenchymal cells. Their presence and accumulation are considered to be a major pathological hallmark of the health and fate of liver parenchymal cells that leads to overall tissue deterioration and eventually results in organ failure. The first description on giant mitochondria dates back to the 1960s, coinciding with the availability of the first generation of electron microscopes in clinical diagnostic laboratories. Detailed accounts on their ultrastructure have mostly been described in patients suffering from alcoholic liver disease, chronic hepatitis, hepatocellular carcinoma and non-alcoholic fatty liver disease. Interestingly, from this extensive literature survey, it became apparent that giant mitochondria or megamitochondria present themselves with or without highly organised crystal-like intramitochondrial inclusions. The origin, formation and potential role of giant mitochondria remain to-date largely unanswered. Likewise, the biochemical composition of the well-organised crystal-like inclusions and their possible impact on mitochondrial function is unclear. Herein, concepts about the possible mechanism of their formation and three-dimensional architecture will be approached. We will furthermore discuss their importance in diagnostics, including future research outlooks and potential therapeutic interventions to cure liver disease where giant mitochondria are implemented.
Topics: Humans; Mitochondrial Swelling; Mitochondria, Liver; Liver Diseases, Alcoholic; Non-alcoholic Fatty Liver Disease; Hepatitis, Chronic; Liver
PubMed: 37615254
DOI: 10.1111/liv.15711 -
Cell Biology and Toxicology Apr 2023Mitochondrial metabolism and function are modulated by changes in matrix Ca. Small increases in the matrix Ca stimulate mitochondrial bioenergetics, whereas excessive Ca...
Mitochondrial metabolism and function are modulated by changes in matrix Ca. Small increases in the matrix Ca stimulate mitochondrial bioenergetics, whereas excessive Ca leads to cell death by causing massive matrix swelling and impairing the structural and functional integrity of mitochondria. Sustained opening of the non-selective mitochondrial permeability transition pores (PTP) is the main mechanism responsible for mitochondrial Ca overload that leads to mitochondrial dysfunction and cell death. Recent studies suggest the existence of two or more types of PTP, and adenine nucleotide translocator (ANT) and FF-ATP synthase were proposed to form the PTP independent of each other. Here, we elucidated the role of ANT in PTP opening by applying both experimental and computational approaches. We first developed and corroborated a detailed model of the ANT transport mechanism including the matrix (ANT), cytosolic (ANT), and pore (ANT) states of the transporter. Then, the ANT model was incorporated into a simple, yet effective, empirical model of mitochondrial bioenergetics to ascertain the point when Ca overload initiates PTP opening via an ANT switch-like mechanism activated by matrix Ca and is inhibited by extra-mitochondrial ADP. We found that encoding a heterogeneous Ca response of at least three types of PTPs, weakly, moderately, and strongly sensitive to Ca, enabled the model to simulate Ca release dynamics observed after large boluses were administered to a population of energized cardiac mitochondria. Thus, this study demonstrates the potential role of ANT in PTP gating and proposes a novel mechanism governing the cryptic nature of the PTP phenomenon.
Topics: Mitochondrial Membrane Transport Proteins; Adenine Nucleotides; Mitochondrial Swelling; Mitochondria; Mitochondrial Permeability Transition Pore; Calcium
PubMed: 35606662
DOI: 10.1007/s10565-022-09724-2 -
Journal of Bioenergetics and... Feb 2017Calcium (Ca) plays diverse roles in all living organisms ranging from bacteria to humans. It is a structural element for bones, an essential mediator of... (Review)
Review
Calcium (Ca) plays diverse roles in all living organisms ranging from bacteria to humans. It is a structural element for bones, an essential mediator of excitation-contraction coupling, and a universal second messenger in the regulation of ion channel, enzyme and gene expression activities. In mitochondria, Ca is crucial for the control of energy production and cellular responses to metabolic stress. Ca uptake by the mitochondria occurs by the uniporter mechanism. The Mitochondrial Ca2+ Uniporter (MCU) protein has recently been identified as a core component responsible for mitochondrial Ca uptake. MCU knockout (MCU KO) studies have identified a number of important roles played by this high capacity uptake pathway. Interestingly, this work has also shown that MCU-mediated Ca uptake is not essential for vital cell functions such as muscle contraction, energy metabolism and neurotransmission. Although mitochondrial Ca uptake was markedly reduced, MCU KO mitochondria still contained low but detectable levels of Ca. In view of the fundamental importance of Ca for basic cell signalling, this finding suggests the existence of other currently unrecognized pathways for Ca entry. We review the experimental evidence for the existence of alternative Ca influx mechanisms and propose how these mechanisms may play an integral role in mitochondrial Ca signalling.
Topics: Calcium; Ion Transport; Metabolic Networks and Pathways; Mitochondria; Mitochondrial Swelling
PubMed: 27665468
DOI: 10.1007/s10863-016-9676-6 -
Shock (Augusta, Ga.) Aug 2023Background: Hyperbilirubinemia is a common perioperative complication, which is associated with acute kidney injury. Bilirubin permeabilizes mitochondrial membranes...
Background: Hyperbilirubinemia is a common perioperative complication, which is associated with acute kidney injury. Bilirubin permeabilizes mitochondrial membranes leading to mitochondrial swelling and dysfunction. In this study, we aimed to determine the association between PINK1-PARKIN-mediated mitophagy and renal ischemia-reperfusion (IR) injury aggravated by hyperbilirubinemia. Methods: A C57BL/6 mouse hyperbilirubinemia model was induced via intraperitoneal injection of bilirubin solution. In addition, a hypoxia/reoxygenation (H/R) injury model of TCMK-1 cells was established. In these models, we determined the effects of hyperbilirubinemia on oxidative stress, apoptosis, mitochondrial damage, and fibrosis. Results:In vitro , colocalization of GFP-LC3 puncta and Mito-Tracker Red showed that the number of mitophagosomes increased in TCMK-1 cells under H/R and bilirubin condition. Silencing of PINK1 or inhibition of autophagy alleviated mitochondrial damage, oxidative stress, and apoptosis in H/R injury aggravated by bilirubin and decreased cell death detected by methyl-thiazolyl-tetrazolium. In vivo , hyperbilirubinemia increased serum creatinine level in the renal IR injury mice model. Hyperbilirubinemia enhanced apoptosis induced by renal IR. In addition, hyperbilirubinemia increased mitophagosomes and autophagosomes and disrupted mitochondrial cristae in the IR kidney. Inhibition of PINK1 or autophagy reduced histological damages by alleviating apoptosis in renal IR injury, aggravated by hyperbilirubinemia. 3-MA or PINK1-shRNA-AAV9 treatment decreased the area of collagen and proteins related to fibrosis in renal IR injury, aggravated by hyperbilirubinemia. Conclusions: We have demonstrated that hyperbilirubinemia aggravated oxidative stress, apoptosis, mitochondrial damage, and fibrosis in renal IR injury by exacerbating PINK1-PARKIN-mediated mitophagy.
Topics: Animals; Mice; Bilirubin; Hyperbilirubinemia; Kidney; Mice, Inbred C57BL; Mitochondria; Mitophagy; Protein Kinases; Reperfusion Injury; Ubiquitin-Protein Ligases
PubMed: 37278995
DOI: 10.1097/SHK.0000000000002160