bims-celmim 2023-09-24 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2023‒09‒24
forty papers selected by
Marc Segarra Mondejar, University of Cologne

Fatty acid oxidation mediated by malonyl-CoA decarboxylase represses renal cell carcinoma progression.
Fructose-induced mTORC1 Activation Promotes Pancreatic Cancer Progression through Inhibition of Autophagy.
Reductive carboxylation epigenetically instructs T cell differentiation.
Spatiotemporally quantitative in vivo imaging of mitochondrial fatty acid β-oxidation at cellular-level resolution in mice.
RNA Interference against ATP as a Gene Therapy Approach for Prostate Cancer.
A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models.
Efficient intervention for pulmonary fibrosis via mitochondrial transfer promoted by mitochondrial biogenesis.
Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction in C. elegans.
Promoting metabolic inefficiency for metabolic disease.
Glucose fluctuation promotes mitochondrial dysfunctions in the cardiomyocyte cell line HL-1.
Construction of a Dual-Emissive Probe for Discriminative Visualization of Lysosomal and Mitochondrial Dysfunction.
Selective retention of dysfunctional mitochondria during asymmetric cell division in yeast.
Oxidative stress induces mitochondrial iron overload and ferroptotic cell death.
Endoplasmic Reticulum Isolation: An Optimized Approach into Cells and Mouse Liver Fractionation.
Nanosecond Pulsed Electric Fields (nsPEFs) Modulate Electron Transport in the Plasma Membrane and the Mitochondria.
Nanodrug regulates ROS homeostasis via enhancing fatty acid oxidation and inhibiting autophagy to overcome tumor drug resistance.
Accumulation of Prion Triggers the Enhanced Glycolysis via Activation of AMKP Pathway in Prion-Infected Rodent and Cell Models.
The Lysosomal Calcium Channel TRPML1 Maintains Mitochondrial Fitness in NK Cells through Interorganelle Cross-Talk.
Mitochondrial transfer restores impaired liver functions by AMPK/ mTOR/PI3K-AKT pathways in metabolic syndrome.
CPT1A-mediated fatty acid oxidation confers cancer cell resistance to immune-mediated cytolytic killing.
Acyl-CoA synthetase expression in human skeletal muscle is reduced in obesity and insulin resistance.
Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout.
Regulation of phosphoglycerate kinase 1 and its critical role in cancer.
Ferroptosis and endoplasmic reticulum stress in ischemic stroke.
The Warburg effect on radioresistance: Survival beyond growth.
Astrocyte metabolism and signaling pathways in the CNS.
Connections between metabolism and epigenetic modifications in cancer.
Mitochondrial transplantation strategies in multifaceted induction of cancer cell death.
Malignant Brain Aging: The Formidable Link Between Dysregulated Signaling Through Mechanistic Target of Rapamycin Pathways and Alzheimer's Disease (Type 3 Diabetes).
Mitochondrial dysfunction at the crossroad of cardiovascular diseases and cancer.
MYC-an emerging player in mitochondrial diseases.
Oxytosis/Ferroptosis in Neurodegeneration: the Underlying Role of Master Regulator Glutathione Peroxidase 4 (GPX4).
Proteotoxic stress and the ubiquitin proteasome system.
Mitochondria pleiotropism in stem cell senescence: Mechanisms and therapeutic approaches.
Cogs in the autophagic machine-equipped to combat dementia-prone neurodegenerative diseases.
Contribution and therapeutic value of mitophagy in cerebral ischemia-reperfusion injury after cardiac arrest.
Mechanistic multiscale modelling of energy metabolism in human astrocytes reveals the impact of morphology changes in Alzheimer's Disease.
Emerging significance and therapeutic targets of ferroptosis: a potential avenue for human kidney diseases.
Dietary fat and lipid metabolism in the tumor microenvironment.
Adiponectin and resistin modulate the progression of Alzheimer´s disease in a metabolic syndrome model.

Cancer Res. 2023 Sep 20.

Fatty acid oxidation mediated by malonyl-CoA decarboxylase represses renal cell carcinoma progression.

Lijie Zhou, Yongbo Luo, Yuenan Liu, Youmiao Zeng, Junwei Tong, Mengting Li, Yaxin Hou, Kaixuan Du, Yabin Qi, Wenbang Pan, Yuanhao Liu, Rongli Wang, Fengyan Tian, Chaohui Gu, Ke Chen.

Fatty acid metabolism reprogramming is a prominent feature of clear cell renal cell carcinoma (ccRCC). Increased lipid storage supports ccRCC progression, highlighting the importance of understanding the molecular mechanisms driving altered fatty acid synthesis in tumors. Here, we identified that malonyl-CoA decarboxylase (MLYCD), a key regulator of fatty acid anabolism, was downregulated in ccRCC, and low expression correlated with poor prognosis in patients. Restoring MLYCD expression in ccRCC cells decreased the content of malonyl CoA, which blocked de novo fatty acid synthesis and promoted fatty acid translocation into mitochondria for oxidation. Inhibition of lipid droplet accumulation induced by MLYCD-mediated fatty acid oxidation disrupted endoplasmic reticulum and mitochondrial homeostasis, increased reactive oxygen species levels, and induced ferroptosis. Moreover, overexpressing MLYCD reduced tumor growth and reversed resistance to sunitinib in vitro and in vivo. Mechanistically, HIF2α inhibited MLYCD translation by upregulating expression of eIF4G3 microexons. Together, this study demonstrates that fatty acid catabolism mediated by MLYCD disrupts lipid homeostasis to repress ccRCC progression. Activating MLYCD-mediated fatty acid metabolism could be a promising therapeutic strategy for treating ccRCC.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-0969
Cancer Res. 2023 Sep 22.

Fructose-induced mTORC1 Activation Promotes Pancreatic Cancer Progression through Inhibition of Autophagy.

Yanfen Cui, Jianfei Tian, Zhaosong Wang, Hui Guo, He Zhang, Zhiyong Wang, Hui Liu, Weijie Song, Liming Liu, Ruinan Tian, Xiaoyan Zuo, Sixin Ren, Ruifang Niu, Fei Zhang.

Excessive fructose intake is associated with the occurrence, progression, and poor prognosis of various tumors. A better understanding of the mechanisms underlying the functions of fructose in cancer could facilitate the development of better treatment and prevention strategies. In this study, we investigated the functional association between fructose utilization and pancreatic ductal adenocarcinoma (PDAC) progression. Fructose could be taken up and metabolized by PDAC cells and provided an adaptive survival mechanism for PDAC cells under glucose deficient conditions. GLUT5-mediated fructose metabolism maintained the survival, proliferation, and invasion capacities of PDAC cells in vivo and in vitro. Fructose metabolism not only provided ATP and biomass to PDAC cells but also conferred metabolic plasticity to the cells, making them more adaptable to the tumor microenvironment. Mechanistically, fructose activated AMPK-mTORC1 signaling pathway to inhibit glucose deficiency-induced autophagic cell death. Moreover, the fructose specific transporter GLUT5 was highly expressed in PDAC tissues and was an independent marker of disease progression in PDAC patients. These findings provide mechanistic insights into the role of fructose in promoting PDAC progression and offer potential strategies for targeting metabolism to treat PDAC.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-0464
Nature. 2023 Sep 20.

Reductive carboxylation epigenetically instructs T cell differentiation.

Alison Jaccard, Tania Wyss, Noelia Maldonado-Pérez, Jan A Rath, Alessio Bevilacqua, Jhan-Jie Peng, Anouk Lepez, Christine Von Gunten, Fabien Franco, Kung-Chi Kao, Nicolas Camviel, Francisco Martín, Bart Ghesquière, Denis Migliorini, Caroline Arber, Pedro Romero, Ping-Chih Ho, Mathias Wenes.

Protective immunity against pathogens or cancer is mediated by the activation and clonal expansion of antigen-specific naive T cells into effector T cells. To sustain their rapid proliferation and effector functions, naive T cells switch their quiescent metabolism to an anabolic metabolism through increased levels of aerobic glycolysis, but also through mitochondrial metabolism and oxidative phosphorylation, generating energy and signalling molecules1-3. However, how that metabolic rewiring drives and defines the differentiation of T cells remains unclear. Here we show that proliferating effector CD8+ T cells reductively carboxylate glutamine through the mitochondrial enzyme isocitrate dehydrogenase 2 (IDH2). Notably, deletion of the gene encoding IDH2 does not impair the proliferation of T cells nor their effector function, but promotes the differentiation of memory CD8+ T cells. Accordingly, inhibiting IDH2 during ex vivo manufacturing of chimeric antigen receptor (CAR) T cells induces features of memory T cells and enhances antitumour activity in melanoma, leukaemia and multiple myeloma. Mechanistically, inhibition of IDH2 activates compensating metabolic pathways that cause a disequilibrium in metabolites regulating histone-modifying enzymes, and this maintains chromatin accessibility at genes that are required for the differentiation of memory T cells. These findings show that reductive carboxylation in CD8+ T cells is dispensable for their effector response and proliferation, but that it mainly produces a pattern of metabolites that epigenetically locks CD8+ T cells into a terminal effector differentiation program. Blocking this metabolic route allows the increased formation of memory T cells, which could be exploited to optimize the therapeutic efficacy of CAR T cells.

DOI: https://doi.org/10.1038/s41586-023-06546-y
Am J Physiol Endocrinol Metab. 2023 Sep 20.

Spatiotemporally quantitative in vivo imaging of mitochondrial fatty acid β-oxidation at cellular-level resolution in mice.

Ayumi Matsumoto, Isao Matsui, Shohei Uchinomiya, Yusuke Katsuma, Seiichi Yasuda, Hiroki Okushima, Atsuhiro Imai, Takeshi Yamamoto, Akio Ojida, Kazunori Inoue, Yoshitaka Isaka.

  Mitochondrial fatty acid β-oxidation (FAO) plays a key role in energy homeostasis. Several FAO evaluation methods are currently available, but they are not necessarily suitable for capturing the dynamics of FAO in vivo at a cellular-level spatial resolution and seconds-level time resolution. FAOBlue is a coumarin-based probe that undergoes β-oxidation to produce a fluorescent substrate, 7-hydroxycoumarin-3-(N-(2-hydroxyethyl))-carboxamide (7-HC). After confirming that 7-HC could be specifically detected using multiphoton microscopy at excitation/emission wavelength = 820/415-485 nm, wild-type C57BL/6 mice were randomly divided into control, pemafibrate, fasting (24 or 72 hours), and etomoxir groups. These mice received a single intravenous injection of FAOBlue. FAO activities in the liver of these mice were visualized using multiphoton microscopy at 4.2 seconds/frame. These approaches could visualize the difference in FAO activities between periportal and pericentral hepatocytes in the control, pemafibrate, and fasting groups. FAO velocity, which was expressed by the maximum slope of the fluorescence intensity curve, was accelerated in the pemafibrate and 72 hours fasting groups both in the periportal and the pericentral hepatocytes in comparison to the control group. Our approach revealed differences in the FAO activation mode by the two stimuli, i.e. pemafibrate and fasting, with pemafibrate accelerating the time of first detection of FAO-derived fluorescence. No increase in the fluorescence was observed in etomoxir-pretreated mice, confirming that FAOBlue specifically detected FAO in vivo. Thus, FAOBlue is useful for visualizing in vivo liver FAO dynamics at the single-cell level spatial resolution and seconds-level time resolution.

Keywords:  Fatty acid β-oxidation; in vivo imaging; liver; spatiotemporal resolution

DOI:  https://doi.org/10.1152/ajpendo.00147.2023
Mol Pharm. 2023 Sep 21.

RNA Interference against ATP as a Gene Therapy Approach for Prostate Cancer.

Shuangya Chen, Jisheng Ma, Yunbei Xiao, Dongyan Zhou, Ping He, Yajing Chen, Xiaolu Zheng, Hui Lin, Feng Qiu, Yuying Yuan, Jiaben Zhong, Xiaokun Li, Xuebo Pan, Zhiyuan Fang, Cong Wang.

  Chemotherapeutic agents targeting energy metabolism have not achieved satisfactory results in different types of tumors. Herein, we developed an RNA interference (RNAi) method against adenosine triphosphate (ATP) by constructing an interfering plasmid-expressing ATP-binding RNA aptamer, which notably inhibited the growth of prostate cancer cells through diminishing the availability of cytoplasmic ATP and impairing the homeostasis of energy metabolism, and both glycolysis and oxidative phosphorylation were suppressed after RNAi treatment. Further identifying the mechanism underlying the effects of ATP aptamer, we surprisingly found that it markedly reduced the activity of membrane ionic channels and membrane potential which led to the dysfunction of mitochondria, such as the decrease of mitochondrial number, reduction in the respiration rate, and decline of mitochondrial membrane potential and ATP production. Meanwhile, the shortage of ATP impeded the formation of lamellipodia that are essential for the movement of cells, consequently resulting in a significant reduction of cell migration. Both the downregulation of the phosphorylation of AMP-activated protein kinase (AMPK) and endoplasmic reticulum kinase (ERK) and diminishing of lamellipodium formation led to cell apoptosis as well as the inhibition of angiogenesis and invasion. In conclusion, as the first RNAi modality targeting the blocking of ATP consumption, the present method can disturb the respiratory chain and ATP pool, which provides a novel regime for tumor therapies..

Keywords:  aptamer; metabolism; mitochondrial function; prostate cancer

DOI:  https://doi.org/10.1021/acs.molpharmaceut.3c00587
PLoS Genet. 2023 Sep;19(9): e1010893

A monocarboxylate transporter rescues frontotemporal dementia and Alzheimer's disease models.

Dongwei Xu, Alec Vincent, Andrés González-Gutiérrez, Benjamin Aleyakpo, Sharifah Anoar, Ashling Giblin, Magda L Atilano, Mirjam Adams, Dunxin Shen, Annora Thoeng, Elli Tsintzas, Marie Maeland, Adrian M Isaacs, Jimena Sierralta, Teresa Niccoli.

Brains are highly metabolically active organs, consuming 20% of a person's energy at resting state. A decline in glucose metabolism is a common feature across a number of neurodegenerative diseases. Another common feature is the progressive accumulation of insoluble protein deposits, it's unclear if the two are linked. Glucose metabolism in the brain is highly coupled between neurons and glia, with glucose taken up by glia and metabolised to lactate, which is then shuttled via transporters to neurons, where it is converted back to pyruvate and fed into the TCA cycle for ATP production. Monocarboxylates are also involved in signalling, and play broad ranging roles in brain homeostasis and metabolic reprogramming. However, the role of monocarboxylates in dementia has not been tested. Here, we find that increasing pyruvate import in Drosophila neurons by over-expression of the transporter bumpel, leads to a rescue of lifespan and behavioural phenotypes in fly models of both frontotemporal dementia and Alzheimer's disease. The rescue is linked to a clearance of late stage autolysosomes, leading to degradation of toxic peptides associated with disease. We propose upregulation of pyruvate import into neurons as potentially a broad-scope therapeutic approach to increase neuronal autophagy, which could be beneficial for multiple dementias.

DOI: https://doi.org/10.1371/journal.pgen.1010893
Nat Commun. 2023 09 18. 14(1): 5781

Efficient intervention for pulmonary fibrosis via mitochondrial transfer promoted by mitochondrial biogenesis.

Ting Huang, Ruyi Lin, Yuanqin Su, Hao Sun, Xixi Zheng, Jinsong Zhang, Xiaoyan Lu, Baiqin Zhao, Xinchi Jiang, Lingling Huang, Ni Li, Jing Shi, Xiaohui Fan, Donghang Xu, Tianyuan Zhang, Jianqing Gao.

The use of exogenous mitochondria to replenish damaged mitochondria has been proposed as a strategy for the treatment of pulmonary fibrosis. However, the success of this strategy is partially restricted by the difficulty of supplying sufficient mitochondria to diseased cells. Herein, we report the generation of high-powered mesenchymal stem cells with promoted mitochondrial biogenesis and facilitated mitochondrial transfer to injured lung cells by the sequential treatment of pioglitazone and iron oxide nanoparticles. This highly efficient mitochondrial transfer is shown to not only restore mitochondrial homeostasis but also reactivate inhibited mitophagy, consequently recovering impaired cellular functions. We perform studies in mouse to show that these high-powered mesenchymal stem cells successfully mitigate fibrotic progression in a progressive fibrosis model, which was further verified in a humanized multicellular lung spheroid model. The present findings provide a potential strategy to overcome the current limitations in mitochondrial replenishment therapy, thereby promoting therapeutic applications for fibrotic intervention.

DOI: https://doi.org/10.1038/s41467-023-41529-7
PLoS Genet. 2023 Sep 18. 19(9): e1010938

Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction in C. elegans.

Hannah J Smith, Anne Lanjuin, Arpit Sharma, Aditi Prabhakar, Ewelina Nowak, Peter G Stine, Rohan Sehgal, Klement Stojanovski, Benjamin D Towbin, William B Mair.

mTORC1 (mechanistic target of rapamycin complex 1) is a metabolic sensor that promotes growth when nutrients are abundant. Ubiquitous inhibition of mTORC1 extends lifespan in multiple organisms but also disrupts several anabolic processes resulting in stunted growth, slowed development, reduced fertility, and disrupted metabolism. However, it is unclear if these pleotropic effects of mTORC1 inhibition can be uncoupled from longevity. Here, we utilize the auxin-inducible degradation (AID) system to restrict mTORC1 inhibition to C. elegans neurons. We find that neuron-specific degradation of RAGA-1, an upstream activator of mTORC1, or LET-363, the ortholog of mammalian mTOR, is sufficient to extend lifespan in C. elegans. Unlike raga-1 loss of function genetic mutations or somatic AID of RAGA-1, neuronal AID of RAGA-1 robustly extends lifespan without impairing body size, developmental rate, brood size, or neuronal function. Moreover, while degradation of RAGA-1 in all somatic tissues alters the expression of thousands of genes, demonstrating the widespread effects of mTORC1 inhibition, degradation of RAGA-1 in neurons only results in around 200 differentially expressed genes with a specific enrichment in metabolism and stress response. Notably, our work demonstrates that targeting mTORC1 specifically in the nervous system in C. elegans uncouples longevity from growth and reproductive impairments, and that many canonical effects of low mTORC1 activity are not required to promote healthy aging. These data challenge previously held ideas about the mechanisms of mTORC1 lifespan extension and underscore the potential of promoting longevity by neuron-specific mTORC1 modulation.

DOI: https://doi.org/10.1371/journal.pgen.1010938
iScience. 2023 Oct 20. 26(10): 107843

Promoting metabolic inefficiency for metabolic disease.

Lawrence Kazak.

  Recent advances in pharmacotherapies that promote appetite suppression have shown remarkable weight loss. Therapies targeting energy expenditure lag behind, and as such none have yet been identified to be safe and efficacious for sustaining negative energy balance toward weight loss. Multiple energy dissipating pathways have been identified in adipose tissue and muscle. The molecular effectors of some of these pathways have been identified, but much is still left to be learned about their regulation. Understanding the molecular underpinnings of metabolic inefficiency in adipose tissue and muscle is required if these pathways are to be therapeutically targeted in the context of obesity and obesity-accelerated diseases.

Keywords:  Human metabolism

DOI:  https://doi.org/10.1016/j.isci.2023.107843
PLoS One. 2023 ;18(9): e0289475

Glucose fluctuation promotes mitochondrial dysfunctions in the cardiomyocyte cell line HL-1.

Patrick Mordel, Fanny Fontaine, Quentin Dupas, Michael Joubert, Stéphane Allouche.

AIMS: Glycemic variability has been suggested as a risk factor for diabetes complications but the precise deleterious mechanisms remain poorly understood. Since mitochondria are the main source of energy in heart and cardiovascular diseases remain the first cause of death in patients with diabetes, the aim of the study was to evaluate the impact of glucose swings on mitochondrial functions in the cardiomyocyte cell line HL-1.METHODS: HL-1 cells were exposed to low (LG, 2.8 mmol/l), normal (NG, 5.5 mmol/l), high (HG, 25 mmol/l) or intermittent high glucose (IHG, swing between low and high) every 2h during 12h (short-time treatment) or every 12h during 72h (long-time treatment). Anaerobic catabolism of glucose was evaluated by measuring glucose consumption and lactate production, oxidative phosphorylation was evaluated by polarography and ATP measurement, mitochondrial superoxide anions and the mitochondrial membrane potential (MMP) were analysed using fluorescent probes, and the protein oxidation was measured by oxyblot.
RESULTS: IHG and HG increased glucose consumption and lactate production compared to LG and NG but without any difference between short- and long-time treatments. After 72h and unlike to LG, NG and HG, we didn't observe any increase of the mitochondrial respiration in the presence of succinate upon IHG treatment. IHG, and to a lesser extent HG, promoted a time-dependent decrease of the mitochondrial membrane potential compared to LG and NG treatments. HG and IHG also increased superoxide anion production compared to LG and NG both at 12 and 72h but with a higher increase for IHG at 72h. At last, both HG and IHG stimulated protein oxidation at 72h compared to LG and NG treatments.
CONCLUSIONS: Our results demonstrated that exposure of HL-1 cells to glucose swings promoted time-dependent mitochondrial dysfunctions suggesting a deleterious effect of such condition in patients with diabetes that could contribute to diabetic cardiomyopathy.

DOI: https://doi.org/10.1371/journal.pone.0289475
Anal Chem. 2023 Sep 19.

Construction of a Dual-Emissive Probe for Discriminative Visualization of Lysosomal and Mitochondrial Dysfunction.

Wei Ge, Huina Wang, Xiaofen Wu, Baoli Dong, Ruoyao Zhang, Minggang Tian.

Discriminatively visualizing mitochondrial and lysosomal dysfunction is crucial for an in-depth understanding of cell apoptosis regulation and relative biology. However, fluorescent probes for the separate visualization of lysosomal and mitochondria damages have not been reported yet. Herein, we have constructed a fluorescent probe [2-(4-hydroxystyryl)-1,3,3-trimethyl-3H-indol-1-ium iodide (HBSI)] for labeling mitochondria and lysosomes in dual emission colors and discriminatively imaging mitochondrial and lysosomal damage in two different sets of fluorescent signals. In living cells, HBSI targeted both lysosomes and mitochondria to give green and red emission, respectively. During mitochondrial damages, HBSI immigrated into lysosomes, and the red emission decreased. During lysosomal damage, HBSI immigrated into mitochondria, and the green emission decreased. With the robust probe, the different damaging sequences of mitochondria and lysosomes under different amounts of H2O2 and chloral hydrate have been revealed. The sequential damage of lysosomes and mitochondria during cell apoptosis induced by rotenone, paclitaxel, and colchicine has been discovered. Furthermore, the regulation of mitochondria, lysosome, and their interplay during autophagy was also observed with the probe.

DOI: https://doi.org/10.1021/acs.analchem.3c03024
PLoS Biol. 2023 Sep 18. 21(9): e3002310

Selective retention of dysfunctional mitochondria during asymmetric cell division in yeast.

Xenia Chelius, Veronika Bartosch, Nathalie Rausch, Magdalena Haubner, Jana Schramm, Ralf J Braun, Till Klecker, Benedikt Westermann.

Decline of mitochondrial function is a hallmark of cellular aging. To counteract this process, some cells inherit mitochondria asymmetrically to rejuvenate daughter cells. The molecular mechanisms that control this process are poorly understood. Here, we made use of matrix-targeted D-amino acid oxidase (Su9-DAO) to selectively trigger oxidative damage in yeast mitochondria. We observed that dysfunctional mitochondria become fusion-incompetent and immotile. Lack of bud-directed movements is caused by defective recruitment of the myosin motor, Myo2. Intriguingly, intact mitochondria that are present in the same cell continue to move into the bud, establishing that quality control occurs directly at the level of the organelle in the mother. The selection of healthy organelles for inheritance no longer works in the absence of the mitochondrial Myo2 adapter protein Mmr1. Together, our data suggest a mechanism in which the combination of blocked fusion and loss of motor protein ensures that damaged mitochondria are retained in the mother cell to ensure rejuvenation of the bud.

DOI: https://doi.org/10.1371/journal.pbio.3002310
Sci Rep. 2023 Sep 19. 13(1): 15515

Oxidative stress induces mitochondrial iron overload and ferroptotic cell death.

Yi Chen, Xiaoyun Guo, Yachang Zeng, Xiaoliang Mo, Siqi Hong, Hui He, Jing Li, Sulail Fatima, Qinghang Liu.

Oxidative stress has been shown to induce cell death in a wide range of human diseases including cardiac ischemia/reperfusion injury, drug induced cardiotoxicity, and heart failure. However, the mechanism of cell death induced by oxidative stress remains incompletely understood. Here we provide new evidence that oxidative stress primarily induces ferroptosis, but not apoptosis, necroptosis, or mitochondria-mediated necrosis, in cardiomyocytes. Intriguingly, oxidative stress induced by organic oxidants such as tert-butyl hydroperoxide (tBHP) and cumene hydroperoxide (CHP), but not hydrogen peroxide (H2O2), promoted glutathione depletion and glutathione peroxidase 4 (GPX4) degradation in cardiomyocytes, leading to increased lipid peroxidation. Moreover, elevated oxidative stress is also linked to labile iron overload through downregulation of the transcription suppressor BTB and CNC homology 1 (Bach1), upregulation of heme oxygenase 1 (HO-1) expression, and enhanced iron release via heme degradation. Strikingly, oxidative stress also promoted HO-1 translocation to mitochondria, leading to mitochondrial iron overload and lipid reactive oxygen species (ROS) accumulation. Targeted inhibition of mitochondrial iron overload or ROS accumulation, by overexpressing mitochondrial ferritin (FTMT) or mitochondrial catalase (mCAT), respectively, markedly inhibited oxidative stress-induced ferroptosis. The levels of mitochondrial iron and lipid peroxides were also markedly increased in cardiomyocytes subjected to simulated ischemia and reperfusion (sI/R) or the chemotherapeutic agent doxorubicin (DOX). Overexpressing FTMT or mCAT effectively prevented cardiomyocyte death induced by sI/R or DOX. Taken together, oxidative stress induced by organic oxidants but not H2O2 primarily triggers ferroptotic cell death in cardiomyocyte through GPX4 and Bach1/HO-1 dependent mechanisms. Our results also reveal mitochondrial iron overload via HO-1 mitochondrial translocation as a key mechanism as well as a potential molecular target for oxidative stress-induced ferroptosis in cardiomyocytes.

DOI: https://doi.org/10.1038/s41598-023-42760-4
Bio Protoc. 2023 Sep 05. 13(17): e4803

Endoplasmic Reticulum Isolation: An Optimized Approach into Cells and Mouse Liver Fractionation.

Marc Leiro, Raúl Ventura, Nil Rojo-Querol, María Isabel Hernández-Alvarez.

  The subfractionation of the endoplasmic reticulum (ER) is a widely used technique in cell biology. However, current protocols present limitations such as low yield, the use of large number of dishes, and contamination with other organelles. Here, we describe an improved method for ER subfractionation that solves other reported methods' main limitations of being time consuming and requiring less starting material. Our protocol involves a combination of different centrifugations and special buffer incubations as well as a fine-tuned method for homogenization followed by western blotting to confirm the purity of the fractions. This protocol contains a method to extract clean ER samples from cells using only five (150 mm) dishes instead of over 50 plates needed in other protocols. In addition, in this article we not only propose a new cell fractionation approach but also an optimized method to isolate pure ER fractions from one mouse liver instead of three, which are commonly used in other protocols. The protocols described here are optimized for time efficiency and designed for seamless execution in any laboratory, eliminating the need for special/patented reagents. Key features • Subcellular fractionation from cells and mouse liver. • Uses only five dishes (150 mm) or one mouse liver to extract highly enriched endoplasmic reticulum without mitochondrial-associated membrane contamination. • These protocols require the use of ultracentrifuges, dounce homogenizers, and/or Teflon Potter Elvehjem. As a result, highly enriched/clean samples are obtained. Graphical overview.

Keywords:  Cells; Endoplasmic reticulum (ER); Mitochondrial-associated membranes (MAMs); Mouse liver; Organelle isolation; Subcellular fractionation; Time efficient

DOI:  https://doi.org/10.21769/BioProtoc.4803
Bioelectrochemistry. 2023 Sep 09. pii: S1567-5394(23)00205-0. [Epub ahead of print]155 108568

Nanosecond Pulsed Electric Fields (nsPEFs) Modulate Electron Transport in the Plasma Membrane and the Mitochondria.

Kamal Asadipour, Maisoun Bani Hani, Lucas Potter, Brittney L Ruedlinger, Nicola Lai, Stephen J Beebe.

  Nanosecond pulsed electric fields (nsPEFs) are a pulsed power technology known for ablating tumors, but they also modulate diverse biological mechanisms. Here we show that nsPEFs regulate trans-plasma membrane electron transport (tPMET) rates in the plasma membrane redox system (PMRS) shown as a reduction of the cell-impermeable, WST-8 tetrazolium dye. At lower charging conditions, nsPEFs enhance, and at higher charging conditions inhibit tPMET in H9c2 non-cancerous cardiac myoblasts and 4T1-luc breast cancer cells. This biphasic nsPEF-induced modulation of tPMET is typical of a hormetic stimulus that is beneficial and stress-adaptive at lower levels and damaging at higher levels. NsPEFs also attenuated mitochondrial electron transport system (ETS) activity (O2 consumption) at Complex I when coupled and uncoupled to oxidative phosphorylation. NsPEFs generated more reactive oxygen species (ROS) in mitochondria (mROS) than in the cytosol (cROS) in non-cancer H9c2 heart cells but more cROS than mROS in 4T1-luc cancer cells. Under lower charging conditions, nsPEFs support glycolysis while under higher charging conditions, nsPEFs inhibit electron transport in the PMRS and the mitochondrial ETS producing ROS, ultimately causing cell death. The impact of nsPEF on ETS presents a new paradigm for considering nsPEF modulation of redox functions, including redox homeostasis and metabolism.

Keywords:  Complex I; Electron Transport System (ETS); Glycolysis; Hormesis; Oxidative Phosphorylation (OxPhos); Oxygen Consumption; Reactive Oxygen Species; Redox Homeostasis; WST-8 tetrazolium dye; trans Plasma Membrane Electron Transport (tPMET)

DOI:  https://doi.org/10.1016/j.bioelechem.2023.108568
Biomater Sci. 2023 Sep 21.

Nanodrug regulates ROS homeostasis via enhancing fatty acid oxidation and inhibiting autophagy to overcome tumor drug resistance.

HaiYang Wang, Minzhao Lin, Gengjia Chen, Zecong Xiao, Xintao Shuai.

The treatment of drug-resistant tumors poses a significant challenge in the field of tumor therapy. Disrupting the homeostasis of reactive oxygen species (ROS) within tumor cells may represent a pivotal strategy for overcoming the prevalent issue of drug resistance. However, the restricted sustainability of ROS generation and the increased autophagy capacity exhibited by tumor cells hinder the application of ROS-based therapies. In this study, we developed liposome nanoparticles (Ato/CQ@L) for co-encapsulation of atorvastatin (Ato), an activator of AMP-activated protein kinase (AMPK), and chloroquine (CQ), an autophagy inhibitor. Upon internalization by tumor cells, Ato upregulated carnitine palmitoyltransferase 1(CPT1) concentration and promoted fatty acid oxidation (FAO) within the tumor cells. The process of FAO coupled with an abundance of fatty acid substrates, facilitates a sustained generation of ROS production. Concurrently, a positive feedback loop is established between escalated concentration of ROS and AMPK protein levels, resulting in a persistent elevation in ROS levels. In addition, CQ disrupted lysosomes, leading to an increased lysosomal pH and reducing autophagy in tumor cells. In both in vivo and in vitro experiments, the Ato/CQ@L treatment group exhibited a considerable enhancement in tumor cell apoptosis, validating the efficacy of this combined therapy. In summary, the combined therapy involving Ato and CQ addresses the inherent limitations of conventional ROS therapy, which include insufficient ROS production and increased autophagy. This approach holds significant potential as a treatment strategy for drug-resistant triple-negative breast cancer.

DOI: https://doi.org/10.1039/d3bm01139a
Mol Neurobiol. 2023 Sep 20.

Accumulation of Prion Triggers the Enhanced Glycolysis via Activation of AMKP Pathway in Prion-Infected Rodent and Cell Models.

Qin Fan, Kang Xiao, Ruhan A, Li-Ping Gao, Yue-Zhang Wu, Dong-Dong Chen, Chao Hu, Xiao-Xi Jia, Chu-Mou Liu, Xin Liu, Cao Chen, Qi Shi, Xiao-Ping Dong.

  Mitochondrial dysfunction is one of the hallmarks in the pathophysiology of prion disease and other neurodegenerative diseases. Various metabolic dysfunctions are identified and considered to contribute to the progression of some types of neurodegenerative diseases. In this study, we evaluated the status of glycolysis pathway in prion-infected rodent and cell models. The levels of the key enzymes, hexokinase (HK), phosphofructokinase (PFK), and pyruvate kinase (PK) were significantly increased, accompanying with markedly downregulated mitochondrial complexes. Double-stained IFAs revealed that the increased HK2 and PFK distributed widely in GFAP-, Iba1-, and NeuN-positive cells. We also identified increased levels of AMP-activated protein kinase (AMPK) and the downstream signaling. Changes of AMPK activity in prion-infected cells by the AMPK-specific inhibitor or activator induced the corresponding alterations not only in the downstream signaling, but also the expressions of three key kinases in glycolysis pathway and the mitochondrial complexes. Transient removal or complete clearance of prion propagation in the prion-infected cells partially but significantly reversed the increases of the key enzymes in glycolysis, the upregulation of AMPK signaling pathway, and the decreases of the mitochondrial complexes. Measurements of the cellular oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) showed lower OCR and higher ECAR in prion-infected cell line, which were sufficiently reversed by clearance of prion propagation. Those data indicate a metabolic reprogramming from oxidative phosphorylation to glycolysis in the brains during the progression of prion disease. Accumulation of PrPSc is critical for the switch to glycolysis, largely via activating AMPK pathway.

Keywords:  AMPK signaling; Glycolysis; Mitochondrial complex; Prion

DOI:  https://doi.org/10.1007/s12035-023-03621-3
J Immunol. 2023 Sep 22. pii: ji2300406. [Epub ahead of print]

The Lysosomal Calcium Channel TRPML1 Maintains Mitochondrial Fitness in NK Cells through Interorganelle Cross-Talk.

Dennis Clement, Edina K Szabo, Silje Zandstra Krokeide, Merete Thune Wiiger, Marianna Vincenti, Daniel Palacios, Young-Tae Chang, Christian Grimm, Sandip Patel, Harald Stenmark, Andreas Brech, Rakesh Kumar Majhi, Karl-Johan Malmberg.

Cytotoxic lymphocytes eliminate cancer cells through the release of lytic granules, a specialized form of secretory lysosomes. This compartment is part of the pleomorphic endolysosomal system and is distinguished by its highly dynamic Ca2+ signaling machinery. Several transient receptor potential (TRP) calcium channels play essential roles in endolysosomal Ca2+ signaling and ensure the proper function of these organelles. In this study, we examined the role of TRPML1 (TRP cation channel, mucolipin subfamily, member 1) in regulating the homeostasis of secretory lysosomes and their cross-talk with mitochondria in human NK cells. We found that genetic deletion of TRPML1, which localizes to lysosomes in NK cells, led to mitochondrial fragmentation with evidence of collapsed mitochondrial cristae. Consequently, TRPML1-/- NK92 (NK92ML1-/-) displayed loss of mitochondrial membrane potential, increased reactive oxygen species stress, reduced ATP production, and compromised respiratory capacity. Using sensitive organelle-specific probes, we observed that mitochondria in NK92ML1-/- cells exhibited evidence of Ca2+ overload. Moreover, pharmacological activation of the TRPML1 channel in primary NK cells resulted in upregulation of LC3-II, whereas genetic deletion impeded autophagic flux and increased accumulation of dysfunctional mitochondria. Thus, TRPML1 impacts autophagy and clearance of damaged mitochondria. Taken together, these results suggest that an intimate interorganelle communication in NK cells is orchestrated by the lysosomal Ca2+ channel TRPML1.

DOI: https://doi.org/10.4049/jimmunol.2300406
Life Sci. 2023 Sep 20. pii: S0024-3205(23)00751-8. [Epub ahead of print] 122116

Mitochondrial transfer restores impaired liver functions by AMPK/ mTOR/PI3K-AKT pathways in metabolic syndrome.

Swati Paliwal, Smita Jain, Pallavi Mudgal, Kanika Verma, Sarvesh Paliwal, Swapnil Sharma.

  AIM: We investigated the effect of mitochondria transfer in high fat diet+streptozotocin (HFD + STZ) induced metabolic syndrome (MeS) in rats. The effect of mitochondria transfer in MeS with co-existing hypertension, hyperlipidaemia, diabetes and fatty liver together, has not been reported.MATERIALS AND METHODS: Heathy mitochondria was transferred intravenously and the effect on several physiological parameters and biochemical parameters were examined in HFD + STZ rats. In addition, RNA-sequencing of healthy liver tissues was performed to elucidate the molecular pathways affected by mitochondria transfer in restoring metabolic health.
KEY FINDINGS: We observed reduction in both systolic and diastolic blood pressure levels, reduced blood glucose levels, and a marked reduction in serum lipid profiles. The levels of alanine transaminase (ALT) and aspartate transaminase (AST) also improved along with evident restoration of liver morphology demonstrated by histopathological analysis. Enhanced mitochondrial biogenetics and reduction in oxidative stress and inflammatory markers was also observed. The pathway enrichment analysis revealed reduction in insulin resistance, inflammatory markers, regulation of mitochondrial bioenergetics, calcium ion homeostasis, fatty-acid β-oxidation, cytokine immune regulators, and enhanced lipid solubilisation. The significant effect of healthy mitochondria transfer in restoration of metabolic functions was observed by the activation of PI3K-AKT, AMPK/mTOR pathways and cytokine immune regulators, suggesting that inflammatory mediators were also significantly affected after mitochondria transfer.
SIGNIFICANCE: This study, provides insights on molecular processes triggered by mitochondria transfer in fatty liver regeneration and improvement of overall metabolic health.

Keywords:  Fatty-acid β oxidation; Metabolic reprogramming; Metabolic syndrome; Mitochondria transplantation; Mitochondrial bioenergetics

DOI:  https://doi.org/10.1016/j.lfs.2023.122116
Proc Natl Acad Sci U S A. 2023 Sep 26. 120(39): e2302878120

CPT1A-mediated fatty acid oxidation confers cancer cell resistance to immune-mediated cytolytic killing.

Zheng Liu, Wenjie Liu, Wei Wang, Yibao Ma, Yufeng Wang, David L Drum, Jinyang Cai, Hallie Blevins, Eun Lee, Syed Shah, Paul B Fisher, Xinhui Wang, Xianjun Fang, Chunqing Guo, Xiang-Yang Wang.

  Although tumor-intrinsic fatty acid β-oxidation (FAO) is implicated in multiple aspects of tumorigenesis and progression, the impact of this metabolic pathway on cancer cell susceptibility to immunotherapy remains unknown. Here, we report that cytotoxicity of killer T cells induces activation of FAO and upregulation of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO in cancer cells. The repression of CPT1A activity or expression renders cancer cells more susceptible to destruction by cytotoxic T lymphocytes. Our mechanistic studies reveal that FAO deficiency abrogates the prosurvival signaling in cancer cells under immune cytolytic stress. Furthermore, we identify T cell-derived IFN-γ as a major factor responsible for induction of CPT1A and FAO in an AMPK-dependent manner, indicating a dynamic interplay between immune effector cells and tumor targets. While cancer growth in the absence of CPT1A remains largely unaffected, established tumors upon FAO inhibition become significantly more responsive to cellular immunotherapies including chimeric antigen receptor-engineered human T cells. Together, these findings uncover a mode of cancer resistance and immune editing that can facilitate immune escape and limit the benefits of immunotherapies.

Keywords:  cancer metabolism; carnitine palmitoyltransferase 1A; cellular immunotherapy; fatty acid oxidation; therapeutic resistance

DOI:  https://doi.org/10.1073/pnas.2302878120
Physiol Rep. 2023 Sep;11(18): e15817

Acyl-CoA synthetase expression in human skeletal muscle is reduced in obesity and insulin resistance.

Margarete Poppelreuther, Anne-Marie Lundsgaard, Pernille Mensberg, Kim Sjøberg, Tina Vilsbøll, Bente Kiens, Joachim Füllekrug.

  Upon intramuscular entry, fatty acids are converted to amphiphatic fatty acyl-CoAs by action of the acyl-CoA synthetase (ACS) enzymes. While it has been reported that insulin resistant skeletal muscle shows an accumulation of fatty acyl-CoAs, the role of the enzymes which catalyze their synthesis is still sparsely studied in human muscle, in particular the influence of obesity, and insulin resistance. We analyzed muscle biopsies obtained from normal weight controls (n = 7, average BMI 24), males/females with obesity (n = 7, average BMI 31), and males/females with obesity and type 2 diabetes (T2D) (n = 7, average BMI 34), for relevant ACS (long-chain acyl-CoA synthetase 1 (ACSL1), -3 (ACSL3) and - 4 (ACSL4), fatty acid transport protein 1 (FATP1) and - 4 (FATP4)). The mRNA expression was determined by real-time PCR, and total oleoyl-CoA synthetase activity was measured. In the males/females with obesity and T2D, the response to 16 weeks of exercise training with minor weight loss was evaluated. ACSL1 is the dominantly expressed ACS isoform in human skeletal muscle. The content of total ACS mRNA, as well as ACSL1 mRNA, were lower in muscle of males/females with obesity and T2D. Exercise training in the males/females with obesity and T2D increased the total ACS enzyme activity, along with a lowering of the HOMA-IR index. The capacity for synthesis of fatty acyl-CoAs is lower in skeletal muscle of obese males/females with T2D. This suggests a decreased ability to convert fatty acids to fatty acyl-CoAs, which in turn may affect their entry into storage or metabolic pathways in muscle. Thus, the accumulation of fatty acyl-CoAs in the obese or insulin resistant state that has been shown in previous reports is not likely to result from increased fatty acid acylation. The upregulation of ACS activity by exercise training appears beneficial and occurred concomitantly with increased insulin sensitivity.

Keywords:  ACSL1; fatty acyl-CoA synthetase activity; human skeletal muscle; insulin resistance; type 2 diabetes

DOI:  https://doi.org/10.14814/phy2.15817
iScience. 2023 Oct 20. 26(10): 107780

Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout.

Margaret E Maes, Gloria Colombo, Florianne E Schoot Uiterkamp, Felix Sternberg, Alessandro Venturino, Elena E Pohl, Sandra Siegert.

  Mitochondrial networks remodel their connectivity, content, and subcellular localization to support optimized energy production in conditions of increased environmental or cellular stress. Microglia rely on mitochondria to respond to these stressors, however our knowledge about mitochondrial networks and their adaptations in microglia in vivo is limited. Here, we generate a mouse model that selectively labels mitochondria in microglia. We identify that mitochondrial networks are more fragmented with increased content and perinuclear localization in vitro vs. in vivo. Mitochondrial networks adapt similarly in microglia closest to the injury site after optic nerve crush. Preventing microglial UCP2 increase after injury by selective knockout induces cellular stress. This results in mitochondrial hyperfusion in male microglia, a phenotype absent in females due to circulating estrogens. Our results establish the foundation for mitochondrial network analysis of microglia in vivo, emphasizing the importance of mitochondrial-based sex effects of microglia in other pathologies.

Keywords:  Biological sciences; Natural sciences; Neuroscience; Physiology; Sensory neuroscience; Systems neuroscience

DOI:  https://doi.org/10.1016/j.isci.2023.107780
Cell Commun Signal. 2023 09 18. 21(1): 240

Regulation of phosphoglycerate kinase 1 and its critical role in cancer.

Kexin Zhang, Lixue Sun, Yuanyuan Kang.

  Cells that undergo normal differentiation mainly rely on mitochondrial oxidative phosphorylation to provide energy, but most tumour cells rely on aerobic glycolysis. This phenomenon is called the "Warburg effect". Phosphoglycerate kinase 1 (PGK1) is a key enzyme in aerobic glycolysis. PGK1 is involved in glucose metabolism as well as a variety of biological activities, including angiogenesis, EMT, mediated autophagy initiation, mitochondrial metabolism, DNA replication and repair, and other processes related to tumorigenesis and development. Recently, an increasing number of studies have proven that PGK1 plays an important role in cancer. In this manuscript, we discussed the effects of the structure, function, molecular mechanisms underlying PGK1 regulation on the initiation and progression of cancer. Additionally, PGK1 is associated with chemotherapy resistance and prognosis in tumour patients. This review presents an overview of the different roles played by PGK1 during tumorigenesis, which will help in the design of experimental studies involving PGK1 and enhance the potential for the use of PGK1 as a therapeutic target in cancer. Video Abstract.

Keywords:  Aerobic glycolysis; Autophagy; EMT; PGK1; Tumorigenesis

DOI:  https://doi.org/10.1186/s12964-023-01256-4
Neural Regen Res. 2024 Mar;19(3): 611-618

Ferroptosis and endoplasmic reticulum stress in ischemic stroke.

Yina Li, Mingyang Li, Shi Feng, Qingxue Xu, Xu Zhang, Xiaoxing Xiong, Lijuan Gu.

  Ferroptosis is a form of non-apoptotic programmed cell death, and its mechanisms mainly involve the accumulation of lipid peroxides, imbalance in the amino acid antioxidant system, and disordered iron metabolism. The primary organelle responsible for coordinating external challenges and internal cell demands is the endoplasmic reticulum, and the progression of inflammatory diseases can trigger endoplasmic reticulum stress. Evidence has suggested that ferroptosis may share pathways or interact with endoplasmic reticulum stress in many diseases and plays a role in cell survival. Ferroptosis and endoplasmic reticulum stress may occur after ischemic stroke. However, there are few reports on the interactions of ferroptosis and endoplasmic reticulum stress with ischemic stroke. This review summarized the recent research on the relationships between ferroptosis and endoplasmic reticulum stress and ischemic stroke, aiming to provide a reference for developing treatments for ischemic stroke.

Keywords:  cell death; endoplasmic reticulum stress; ferroptosis; ischemic stroke; lipid peroxidation

DOI:  https://doi.org/10.4103/1673-5374.380870
Biochim Biophys Acta Rev Cancer. 2023 Sep 17. pii: S0304-419X(23)00137-3. [Epub ahead of print] 188988

The Warburg effect on radioresistance: Survival beyond growth.

Hyunkoo Kang, Byeongsoo Kim, Junhyeong Park, HyeSook Youn, BuHyun Youn.

  The Warburg effect is a phenomenon in which cancer cells rely primarily on glycolysis rather than oxidative phosphorylation, even in the presence of oxygen. Although evidence of its involvement in cell proliferation has been discovered, the advantages of the Warburg effect in cancer cell survival under treatment have not been fully elucidated. In recent years, the metabolic characteristics of radioresistant cancer cells have been evaluated, enabling an extension of the original concept of the Warburg effect. In this review, we focused on the role of the Warburg effect in redox homeostasis and DNA damage repair, two critical factors contributing to radioresistance. In addition, we highlighted the metabolic involvement in the radioresistance of cancer stem cells, which is the root cause of tumor recurrence. Finally, we summarized radiosensitizing drugs that target the Warburg effect. Insights into the molecular mechanisms underlying the Warburg effect and radioresistance can provide valuable information for developing strategies to enhance the efficacy of radiotherapy and provide future directions for successful cancer therapy.

Keywords:  DNA damage repair; Warburg effect; radioresistance; redox homeostasis

DOI:  https://doi.org/10.1016/j.bbcan.2023.188988
Front Neurosci. 2023 ;17 1217451

Astrocyte metabolism and signaling pathways in the CNS.

Yong-Mei Zhang, Ying-Bei Qi, Ya-Nan Gao, Wen-Gang Chen, Ting Zhou, Yi Zang, Jia Li.

  Astrocytes comprise half of the cells in the central nervous system and play a critical role in maintaining metabolic homeostasis. Metabolic dysfunction in astrocytes has been indicated as the primary cause of neurological diseases, such as depression, Alzheimer's disease, and epilepsy. Although the metabolic functionalities of astrocytes are well known, their relationship to neurological disorders is poorly understood. The ways in which astrocytes regulate the metabolism of glucose, amino acids, and lipids have all been implicated in neurological diseases. Metabolism in astrocytes has also exhibited a significant influence on neuron functionality and the brain's neuro-network. In this review, we focused on metabolic processes present in astrocytes, most notably the glucose metabolic pathway, the fatty acid metabolic pathway, and the amino-acid metabolic pathway. For glucose metabolism, we focused on the glycolysis pathway, pentose-phosphate pathway, and oxidative phosphorylation pathway. In fatty acid metabolism, we followed fatty acid oxidation, ketone body metabolism, and sphingolipid metabolism. For amino acid metabolism, we summarized neurotransmitter metabolism and the serine and kynurenine metabolic pathways. This review will provide an overview of functional changes in astrocyte metabolism and provide an overall perspective of current treatment and therapy for neurological disorders.

Keywords:  astrocyte; energy imbalance; metabolism; neural circuit; neurological disorders

DOI:  https://doi.org/10.3389/fnins.2023.1217451
Med Rev (Berl). 2021 Dec;1(2): 199-221

Connections between metabolism and epigenetic modifications in cancer.

Guangchao Wang, Jingdong J Han.

  How cells sense and respond to environmental changes is still a key question. It has been identified that cellular metabolism is an important modifier of various epigenetic modifications, such as DNA methylation, histone methylation and acetylation and RNA N6-methyladenosine (m6A) methylation. This closely links the environmental nutrient availability to the maintenance of chromatin structure and gene expression, and is crucial to regulate cellular homeostasis, cell growth and differentiation. Cancer metabolic reprogramming and epigenetic alterations are widely observed, and facilitate cancer development and progression. In cancer cells, oncogenic signaling-driven metabolic reprogramming modifies the epigenetic landscape via changes in the key metabolite levels. In this review, we briefly summarized the current evidence that the abundance of key metabolites, such as S-adenosyl methionine (SAM), acetyl-CoA, α-ketoglutarate (α-KG), 2-hydroxyglutarate (2-HG), uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) and lactate, affected by metabolic reprogramming plays an important role in dynamically regulating epigenetic modifications in cancer. An improved understanding of the roles of metabolic reprogramming in epigenetic regulation can contribute to uncover the underlying mechanisms of metabolic reprogramming in cancer development and identify the potential targets for cancer therapies.

Keywords:  DNA methylation; RNA m6A; cancer metabolic reprogramming; epigenetic modifications; histone acetylation; histone methylation

DOI:  https://doi.org/10.1515/mr-2021-0015
Life Sci. 2023 Sep 19. pii: S0024-3205(23)00733-6. [Epub ahead of print] 122098

Mitochondrial transplantation strategies in multifaceted induction of cancer cell death.

Alfredo Cruz-Gregorio, Ana Karina Aranda-Rivera, Isabel Amador-Martinez, Paola Maycotte.

  Otto Warburg hypothesized that some cancer cells reprogram their metabolism, favoring glucose metabolism by anaerobic glycolysis (Warburg effect) instead of oxidative phosphorylation, mainly because the mitochondria of these cells were damaged or dysfunctional. It should be noted that mitochondrial apoptosis is decreased because of the dysfunctional mitochondria. Strategies like mitochondrial transplantation therapy, where functional mitochondria are transplanted to cancer cells, could increase cell death, such as apoptosis because the intrinsic apoptosis mechanisms would be reactivated. In addition, mitochondrial transplantation is associated with the redox state, which could promote synergy with common anticancer treatments such as ionizing radiation, chemotherapy, or radiotherapy, increasing cell death due to the presence or decrease of oxidative stress. On the other hand, mitochondrial transfer, a natural process for sharing mitochondrial between cells, induces an increase in chemoresistance and invasiveness in cancer cells that receive mitochondria from cells of the tumor microenvironment (TME), which indicates an antitumor therapeutic target. This review focuses on understanding mitochondrial transplantation as a therapeutic outcome induced by a procedure in aspects including oxidative stress, metabolism shifting, mitochondrial function, auto-/mitophagy, invasiveness, and chemoresistance. It also explores how these mechanisms, such as apoptosis, necroptosis, and parthanatos, impact cell death pathways.

Keywords:  Apoptosis; Autophagy; Induction of cancer death; Mitochondrial transfer; Mitochondrial transplantation; Necroptosis; Oxidative stress

DOI:  https://doi.org/10.1016/j.lfs.2023.122098
J Alzheimers Dis. 2023 Sep 11.

Malignant Brain Aging: The Formidable Link Between Dysregulated Signaling Through Mechanistic Target of Rapamycin Pathways and Alzheimer's Disease (Type 3 Diabetes).

Suzanne M de la Monte.

  Malignant brain aging corresponds to accelerated age-related declines in brain functions eventually derailing the self-sustaining forces that govern independent vitality. Malignant brain aging establishes the path toward dementing neurodegeneration, including Alzheimer's disease (AD). The full spectrum of AD includes progressive dysfunction of neurons, oligodendrocytes, astrocytes, microglia, and the microvascular systems, and is mechanistically driven by insulin and insulin-like growth factor (IGF) deficiencies and resistances with accompanying deficits in energy balance, increased cellular stress, inflammation, and impaired perfusion, mimicking the core features of diabetes mellitus. The underlying pathophysiological derangements result in mitochondrial dysfunction, abnormal protein aggregation, increased oxidative and endoplasmic reticulum stress, aberrant autophagy, and abnormal post-translational modification of proteins, all of which are signature features of both AD and dysregulated insulin/IGF-1-mechanistic target of rapamycin (mTOR) signaling. This article connects the dots from benign to malignant aging to neurodegeneration by reviewing the salient pathologies associated with initially adaptive and later dysfunctional mTOR signaling in the brain. Effective therapeutic and preventive measures must be two-pronged and designed to 1) address complex and shifting impairments in mTOR signaling through the re-purpose of effective anti-diabetes therapeutics that target the brain, and 2) minimize the impact of extrinsic mediators of benign to malignant aging transitions, e.g., inflammatory states, obesity, systemic insulin resistance diseases, and repeated bouts of general anesthesia, by minimizing exposures or implementing neuroprotective measures.

Keywords:  Aging; Alzheimer’s disease; brain; mTOR; neurodegeneration; neuroinflammation; type 3 diabetes; vascular disease; white matter

DOI:  https://doi.org/10.3233/JAD-230555
J Transl Med. 2023 Sep 19. 21(1): 635

Mitochondrial dysfunction at the crossroad of cardiovascular diseases and cancer.

Carmine Rocca, Teresa Soda, Ernestina Marianna De Francesco, Marco Fiorillo, Francesco Moccia, Giuseppe Viglietto, Tommaso Angelone, Nicola Amodio.

  A large body of evidence indicates the existence of a complex pathophysiological relationship between cardiovascular diseases and cancer. Mitochondria are crucial organelles whose optimal activity is determined by quality control systems, which regulate critical cellular events, ranging from intermediary metabolism and calcium signaling to mitochondrial dynamics, cell death and mitophagy. Emerging data indicate that impaired mitochondrial quality control drives myocardial dysfunction occurring in several heart diseases, including cardiac hypertrophy, myocardial infarction, ischaemia/reperfusion damage and metabolic cardiomyopathies. On the other hand, diverse human cancers also dysregulate mitochondrial quality control to promote their initiation and progression, suggesting that modulating mitochondrial homeostasis may represent a promising therapeutic strategy both in cardiology and oncology. In this review, first we briefly introduce the physiological mechanisms underlying the mitochondrial quality control system, and then summarize the current understanding about the impact of dysregulated mitochondrial functions in cardiovascular diseases and cancer. We also discuss key mitochondrial mechanisms underlying the increased risk of cardiovascular complications secondary to the main current anticancer strategies, highlighting the potential of strategies aimed at alleviating mitochondrial impairment-related cardiac dysfunction and tumorigenesis. It is hoped that this summary can provide novel insights into precision medicine approaches to reduce cardiovascular and cancer morbidities and mortalities.

Keywords:  Anticancer therapy; Cancer; Cardiotoxicity; Cardiovascular diseases; Mitochondrial dynamics; Mitochondrial dysfunction

DOI:  https://doi.org/10.1186/s12967-023-04498-5
Front Cell Dev Biol. 2023 ;11 1257651

MYC-an emerging player in mitochondrial diseases.

Janne Purhonen, Juha Klefström, Jukka Kallijärvi.

  The mitochondrion is a major hub of cellular metabolism and involved directly or indirectly in almost all biological processes of the cell. In mitochondrial diseases, compromised respiratory electron transfer and oxidative phosphorylation (OXPHOS) lead to compensatory rewiring of metabolism with resemblance to the Warburg-like metabolic state of cancer cells. The transcription factor MYC (or c-MYC) is a major regulator of metabolic rewiring in cancer, stimulating glycolysis, nucleotide biosynthesis, and glutamine utilization, which are known or predicted to be affected also in mitochondrial diseases. Albeit not widely acknowledged thus far, several cell and mouse models of mitochondrial disease show upregulation of MYC and/or its typical transcriptional signatures. Moreover, gene expression and metabolite-level changes associated with mitochondrial integrated stress response (mt-ISR) show remarkable overlap with those of MYC overexpression. In addition to being a metabolic regulator, MYC promotes cellular proliferation and modifies the cell cycle kinetics and, especially at high expression levels, promotes replication stress and genomic instability, and sensitizes cells to apoptosis. Because cell proliferation requires energy and doubling of the cellular biomass, replicating cells should be particularly sensitive to defective OXPHOS. On the other hand, OXPHOS-defective replicating cells are predicted to be especially vulnerable to high levels of MYC as it facilitates evasion of metabolic checkpoints and accelerates cell cycle progression. Indeed, a few recent studies demonstrate cell cycle defects and nuclear DNA damage in OXPHOS deficiency. Here, we give an overview of key mitochondria-dependent metabolic pathways known to be regulated by MYC, review the current literature on MYC expression in mitochondrial diseases, and speculate how its upregulation may be triggered by OXPHOS deficiency and what implications this has for the pathogenesis of these diseases.

Keywords:  Warburg effect; cellular senescence; electron transport chain; mitochondrial integrated stress response; oxidative phosphorylation; respiratory complex III

DOI:  https://doi.org/10.3389/fcell.2023.1257651
Mol Neurobiol. 2023 Sep 19.

Oxytosis/Ferroptosis in Neurodegeneration: the Underlying Role of Master Regulator Glutathione Peroxidase 4 (GPX4).

Nawab John Dar, Urmilla John, Nargis Bano, Sameera Khan, Shahnawaz Ali Bhat.

  Oxytosis/ferroptosis is an iron-dependent oxidative form of cell death triggered by lethal accumulation of phospholipid hydroperoxides (PLOOHs) in membranes. Failure of the intricate PLOOH repair system is a principle cause of ferroptotic cell death. Glutathione peroxidase 4 (GPX4) is distinctly vital for converting PLOOHs in membranes to non-toxic alcohols. As such, GPX4 is known as the master regulator of oxytosis/ferroptosis. Ferroptosis has been implicated in a number of disorders such as neurodegenerative diseases (amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), etc.), ischemia/reperfusion injury, and kidney degeneration. Reduced function of GPX4 is frequently observed in degenerative disorders. In this study, we examine how diminished GPX4 function may be a critical event in triggering oxytosis/ferroptosis to perpetuate or initiate the neurodegenerative diseases and assess the possible therapeutic importance of oxytosis/ferroptosis in neurodegenerative disorders. These discoveries are important for advancing our understanding of neurodegenerative diseases because oxytosis/ferroptosis may provide a new target to slow the course of the disease.

Keywords:  AD; ALS; GPX4; Lipid peroxidation; Neurodegeneration; Oxidative stress; Oxytosis/ferroptosis; PD

DOI:  https://doi.org/10.1007/s12035-023-03646-8
Semin Cell Dev Biol. 2023 Sep 19. pii: S1084-9521(23)00161-1. [Epub ahead of print]

Proteotoxic stress and the ubiquitin proteasome system.

Rachel Kandel, Jasmine Jung, Sonya Neal.

  The ubiquitin proteasome system maintains protein homeostasis by regulating the breakdown of misfolded proteins, thereby preventing misfolded protein aggregates. The efficient elimination is vital for preventing damage to the cell by misfolded proteins, known as proteotoxic stress. Proteotoxic stress can lead to the collapse of protein homeostasis and can alter the function of the ubiquitin proteasome system. Conversely, impairment of the ubiquitin proteasome system can also cause proteotoxic stress and disrupt protein homeostasis. This review examines two impacts of proteotoxic stress, 1) disruptions to ubiquitin homeostasis (ubiquitin stress) and 2) disruptions to proteasome homeostasis (proteasome stress). Here, we provide a mechanistic description of the relationship between proteotoxic stress and the ubiquitin proteasome system. This relationship is illustrated by findings from several protein misfolding diseases, mainly neurodegenerative diseases, as well as from basic biology discoveries from yeast to mammals. In addition, we explore the importance of the ubiquitin proteasome system in endoplasmic reticulum quality control, and how proteotoxic stress at this organelle is alleviated. Finally, we highlight how cells utilize the ubiquitin proteasome system to adapt to proteotoxic stress and how the ubiquitin proteasome system can be genetically and pharmacologically manipulated to maintain protein homeostasis.

Keywords:  Aggregates; Deubiquitinase; Neurodegeneration; Nrf1; Proteasome; Proteasome stress; Protein misfolding; Proteotoxic stress; Ubiquitin; Ubiquitin proteasome system; Ubiquitin stress; Unfolded protein response; Usp14

DOI:  https://doi.org/10.1016/j.semcdb.2023.08.002
Free Radic Biol Med. 2023 Sep 20. pii: S0891-5849(23)00643-3. [Epub ahead of print]

Mitochondria pleiotropism in stem cell senescence: Mechanisms and therapeutic approaches.

Cristina Mas-Bargues.

  Aging is a complex biological process characterized by a progressive decline in cellular and tissue function, ultimately leading to organismal aging. Stem cells, with their regenerative potential, play a crucial role in maintaining tissue homeostasis and repair throughout an organism's lifespan. Mitochondria, the powerhouses of the cell, have emerged as key players in the aging process, impacting stem cell function and contributing to age-related tissue dysfunction. Here are discuss the mechanisms through which mitochondria influence stem cell fate decisions, including energy production, metabolic regulation, ROS signalling, and epigenetic modifications. Therefore, this review highlights the role of mitochondria in driving stem cell senescence and the subsequent impact on tissue function, leading to overall organismal aging and age-related diseases. Finally, we explore potential anti-aging therapies targeting mitochondrial health and discuss their implications for promoting healthy aging. This comprehensive review sheds light on the critical interplay between mitochondrial function, stem cell senescence, and organismal aging, offering insights into potential strategies for attenuating age-related decline and promoting healthy longevity.

Keywords:  Aging; Anti-aging therapies; Mitochondria; Senescence; Stem cells

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.09.019
Front Mol Neurosci. 2023 ;16 1225227

Cogs in the autophagic machine-equipped to combat dementia-prone neurodegenerative diseases.

Sholto de Wet, Rensu Theart, Ben Loos.

  Neurodegenerative diseases are often characterized by hydrophobic inclusion bodies, and it may be the case that the aggregate-prone proteins that comprise these inclusion bodies are in fact the cause of neurotoxicity. Indeed, the appearance of protein aggregates leads to a proteostatic imbalance that causes various interruptions in physiological cellular processes, including lysosomal and mitochondrial dysfunction, as well as break down in calcium homeostasis. Oftentimes the approach to counteract proteotoxicity is taken to merely upregulate autophagy, measured by an increase in autophagosomes, without a deeper assessment of contributors toward effective turnover through autophagy. There are various ways in which autophagy is regulated ranging from the mammalian target of rapamycin (mTOR) to acetylation status of proteins. Healthy mitochondria and the intracellular energetic charge they preserve are key for the acidification status of lysosomes and thus ensuring effective clearance of components through the autophagy pathway. Both mitochondria and lysosomes have been shown to bear functional protein complexes that aid in the regulation of autophagy. Indeed, it may be the case that minimizing the proteins associated with the respective neurodegenerative pathology may be of greater importance than addressing molecularly their resulting inclusion bodies. It is in this context that this review will dissect the autophagy signaling pathway, its control and the manner in which it is molecularly and functionally connected with the mitochondrial and lysosomal system, as well as provide a summary of the role of autophagy dysfunction in driving neurodegenerative disease as a means to better position the potential of rapamycin-mediated bioactivities to control autophagy favorably.

Keywords:  autophagy; lysosomes; mitochondrial function; mitophagy; neurodegenerative diseases; proteostasis

DOI:  https://doi.org/10.3389/fnmol.2023.1225227
Biomed Pharmacother. 2023 Sep 14. pii: S0753-3322(23)01290-8. [Epub ahead of print]167 115492

Contribution and therapeutic value of mitophagy in cerebral ischemia-reperfusion injury after cardiac arrest.

Zheng Li, Jihong Xing.

  Cardiopulmonary resuscitation and related life support technologies have improved substantially in recent years; however, mortality and disability rates from cardiac arrest (CA) remain high and are closely associated with the high incidence of cerebral ischemia-reperfusion injury (CIRI), which is explained by a "double-hit" model (i.e., resulting from both ischemia and reperfusion). Mitochondria are important power plants in the cell and participate in various biochemical processes, such as cell differentiation and signaling in eukaryotes. Various mitochondrial processes, including energy metabolism, calcium homeostasis, free radical production, and apoptosis, are involved in several important stages of the progression and development of CIRI. Mitophagy is a key mechanism of the endogenous removal of damaged mitochondria to maintain organelle function and is a critical target for CIRI treatment after CA. Mitophagy also plays an essential role in attenuating ischemia-reperfusion in other organs, particularly during post-cardiac arrest myocardial dysfunction. Regulation of mitophagy may influence necroptosis (a programmed cell death pathway), which is the main endpoint of organ ischemia-reperfusion injury. In this review, we summarize the main signaling pathways related to mitophagy and their associated regulatory proteins. New therapeutic methods and drugs targeting mitophagy in ischemia-reperfusion animal models are also discussed. In-depth studies of the mechanisms underlying the regulation of mitophagy will enhance our understanding of the damage and repair processes in CIRI after CA, thereby contributing to the development of new therapeutic strategies.

Keywords:  Cardiac arrest; Cerebral ischemia and reperfusion; Mitophagy; PINK1/Parkin

DOI:  https://doi.org/10.1016/j.biopha.2023.115492
PLoS Comput Biol. 2023 Sep 20. 19(9): e1011464

Mechanistic multiscale modelling of energy metabolism in human astrocytes reveals the impact of morphology changes in Alzheimer's Disease.

Sofia Farina, Valérie Voorsluijs, Sonja Fixemer, David Bouvier, Susanne Claus, Mark Ellisman, Stéphane P A Bordas, Alexander Skupin.

Astrocytes with their specialised morphology are essential for brain homeostasis as metabolic mediators between blood vessels and neurons. In neurodegenerative diseases such as Alzheimer's disease (AD), astrocytes adopt reactive profiles with molecular and morphological changes that could lead to the impairment of their metabolic support and impact disease progression. However, the underlying mechanisms of how the metabolic function of human astrocytes is impaired by their morphological changes in AD are still elusive. To address this challenge, we developed and applied a metabolic multiscale modelling approach integrating the dynamics of metabolic energy pathways and physiological astrocyte morphologies acquired in human AD and age-matched control brain samples. The results demonstrate that the complex cell shape and intracellular organisation of energetic pathways determine the metabolic profile and support capacity of astrocytes in health and AD conditions. Thus, our mechanistic approach indicates the importance of spatial orchestration in metabolism and allows for the identification of protective mechanisms against disease-associated metabolic impairments.

DOI: https://doi.org/10.1371/journal.pcbi.1011464
Cell Death Dis. 2023 Sep 22. 14(9): 628

Emerging significance and therapeutic targets of ferroptosis: a potential avenue for human kidney diseases.

Jinghan Li, Sujuan Zheng, Yumei Fan, Ke Tan.

Kidney diseases remain one of the leading causes of human death and have placed a heavy burden on the medical system. Regulated cell death contributes to the pathology of a plethora of renal diseases. Recently, with in-depth studies into kidney diseases and cell death, a new iron-dependent cell death modality, known as ferroptosis, has been identified and has attracted considerable attention among researchers in the pathogenesis of kidney diseases and therapeutics to treat them. The majority of studies suggest that ferroptosis plays an important role in the pathologies of multiple kidney diseases, such as acute kidney injury (AKI), chronic kidney disease, and renal cell carcinoma. In this review, we summarize recently identified regulatory molecular mechanisms of ferroptosis, discuss ferroptosis pathways and mechanisms of action in various kidney diseases, and describe the protective effect of ferroptosis inhibitors against kidney diseases, especially AKI. By summarizing the prominent roles of ferroptosis in different kidney diseases and the progress made in studying ferroptosis, we provide new directions and strategies for future research on kidney diseases. In summary, ferroptotic factors are potential targets for therapeutic intervention to alleviate different kidney diseases, and targeting them may lead to new treatments for patients with kidney diseases.

DOI: https://doi.org/10.1038/s41419-023-06144-w
Biochim Biophys Acta Rev Cancer. 2023 Sep 16. pii: S0304-419X(23)00133-6. [Epub ahead of print] 188984

Dietary fat and lipid metabolism in the tumor microenvironment.

Swagata Goswami, Qiming Zhang, Cigdem Elif Celik, Ethan M Reich, Ömer H Yilmaz.

  Metabolic reprogramming has been considered a core hallmark of cancer, in which excessive accumulation of lipids promote cancer initiation, progression and metastasis. Lipid metabolism is often considered as the digestion and absorption process of dietary fat, and the ways in which cancer cells utilize lipids are often influenced by the complex interactions within the tumor microenvironment. Among multiple cancer risk factors, obesity has a positive association with multiple cancer types, while diets like calorie restriction and fasting improve health and delay cancer. Impact of these diets on tumorigenesis or cancer prevention are generally studied on cancer cells, despite heterogeneity of the tumor microenvironment. Cancer cells regularly interact with these heterogeneous microenvironmental components, including immune and stromal cells, to promote cancer progression and metastasis, and there is an intricate metabolic crosstalk between these compartments. Here, we focus on discussing fat metabolism and response to dietary fat in the tumor microenvironment, focusing on both immune and stromal components and shedding light on therapeutic strategies surrounding lipid metabolic and signaling pathways.

Keywords:  Fatty acid; High fat diet; Immunosuppression; Lipid metabolism; Obesity; Therapeutic intervention; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2023.188984
Front Endocrinol (Lausanne). 2023 ;14 1237796

Adiponectin and resistin modulate the progression of Alzheimer´s disease in a metabolic syndrome model.

Pedro Cisternas, Camila Gherardelli, Joel Gutierrez, Paulina Salazar, Carolina Mendez-Orellana, G William Wong, Nibaldo C Inestrosa.

  Metabolic syndrome (MetS), a cluster of metabolic conditions that include obesity, hyperlipidemia, and insulin resistance, increases the risk of several aging-related brain diseases, including Alzheimer's disease (AD). However, the underlying mechanism explaining the link between MetS and brain function is poorly understood. Among the possible mediators are several adipose-derived secreted molecules called adipokines, including adiponectin (ApN) and resistin, which have been shown to regulate brain function by modulating several metabolic processes. To investigate the impact of adipokines on MetS, we employed a diet-induced model to induce the various complications associated with MetS. For this purpose, we administered a high-fat diet (HFD) to both WT and APP/PSN1 mice at a pre-symptomatic disease stage. Our data showed that MetS causes a fast decline in cognitive performance and stimulates Aβ42 production in the brain. Interestingly, ApN treatment restored glucose metabolism and improved cognitive functions by 50% while decreasing the Aβ42/40 ratio by approximately 65%. In contrast, resistin exacerbated Aβ pathology, increased oxidative stress, and strongly reduced glucose metabolism. Together, our data demonstrate that ApN and resistin alterations could further contribute to AD pathology.

Keywords:  Alzheimer´s disease; adiponectin; glucose metabolism; obesity; resistin

DOI:  https://doi.org/10.3389/fendo.2023.1237796