bims-celmim 2023-08-13 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2023–08–13
thirteen papers selected by
Marc Segarra Mondejar, University of Cologne

The ubiquitin-proteasome system links NADPH metabolism to ferroptosis.
An implication of the mitochondrial carrier SLC25A3 as an oxidative stress modulator in NAFLD.
The emerging era of lactate: A rising star in cellular signaling and its regulatory mechanisms.
Glucose Deprivation Induces Cancer Cell Death through Failure of ROS Regulation.
Exploring Molecular Targets for Mitochondrial Therapies in Neurodegenerative Diseases.
Glutathionylation of pyruvate dehydrogenase complex E2 and inflammatory cytokine production during acute inflammation are magnified by mitochondrial oxidative stress.
AMPD2 plays important roles in regulating hepatic glucose and lipid metabolism.
ACOT1 deficiency attenuates high-fat diet induced fat mass gain by increasing energy expenditure.
Loss and recovery of myocardial mitochondria in mice under different tail suspension time: Apoptosis and mitochondrial fission, fusion and autophagy.
TNIK is a conserved regulator of glucose and lipid metabolism in obesity.
The Role of Intracellular Ca2+ and Mitochondrial ROS in Small Aβ1-42 Oligomer-Induced Microglial Death.
Alterations in Mitochondrial Morphology and Quality Control in Primary Mouse Lung Microvascular Endothelial Cells and Human Dermal Fibroblasts under Hyperglycemic Conditions.
A novel role for astrocytic fragmented mitochondria in regulating morphine addiction.

Trends Cell Biol. 2023 Aug 07. pii: S0962-8924(23)00136-8. [Epub ahead of print]

The ubiquitin-proteasome system links NADPH metabolism to ferroptosis.

Jihye Yang, Yoontae Lee, Cheol-Sang Hwang.

  Ferroptosis is the type of cell death arising from uncontrolled and excessive lipid peroxidation. NADPH is essential for ferroptosis regulation because it supplies reducing equivalents for antioxidant defense systems and contributes to the generation of reactive oxygen species. Moreover, NADPH level serves as a biomarker for predicting the sensitivity of cells to ferroptosis. The ubiquitin-proteasome system governs the stability of many ferroptosis effectors. Recent research has revealed MARCHF6, the endoplasmic reticulum ubiquitin ligase, as an unprecedented NADPH sensor in the ubiquitin system and a critical regulator of ferroptosis involved in tumorigenesis and fetal development. This review summarizes the current understanding of NADPH metabolism and the ubiquitin-proteasome system in regulating ferroptosis and highlights the emerging importance of MARCHF6 as a vital connector between NADPH metabolism and ferroptosis.

Keywords:  MARCHF6 E3 ligase; NADPH; cell death; ferroptosis; ubiquitin–proteasome system

DOI:  https://doi.org/10.1016/j.tcb.2023.07.003
Exp Cell Res. 2023 Aug 07. pii: S0014-4827(23)00288-4. [Epub ahead of print] 113740

An implication of the mitochondrial carrier SLC25A3 as an oxidative stress modulator in NAFLD.

Takeo Nakanishi, Yuki Kawasaki, Yoshinobu Nakamura, Yuuki Kimura, Kotone Kawamura, Melody N Shumba, Noriaki Shimokawa.

  Nonalcoholic fatty liver disease (NAFLD) is a type of steatosis not associated with excessive alcohol intake and includes nonalcoholic steatohepatitis (NASH), which can progress to advanced fibrosis and hepatocellular carcinoma. Mitochondrial dysfunction causes oxidative stress, triggering hepatocyte death and inflammation; therefore, the present study aimed to explore relationship between mitochondrial carriers and oxidative stress. Firstly, we established a high fat diet (HFD)-fed ICR mouse NAFLD model characterized by obesity with insulin resistance and found transcriptional upregulation of Slc25a17 and downregulation of Slc25a3 (isoform B) and Slc25a13 in their fatty liver. A mitochondrial phosphate and Cu carrier, SLC25A3, was further studied in wild-type (wt) and SLC25A3-defective HepG2 cells (C1 and C3). SLC25A3 deficiency had insignificant effect on mitochondrial membrane potential (MtMP) and oxygen consumption rate (OCR) in untreated cells but suppressed them when cells were exposed to oleic acids. C1 and C3 cells were prone to produce reactive oxygen species (ROS), and increased ROS was associated with reduced mRNA expression of glutathione peroxidase (GPX) 1 and glutathione disulfide reductase (GSX) in these cell lines. Interestingly, cytoplasmic and mitochondrial Cu accumulation significantly reduced in C1 cells, demonstrating a predominant contribution of SLC25A3 to Cu transport into mitochondrial matrix. Cytotoxicity of free fatty acids was unchanged between wt and SLC25A3-deficient cells. These results indicate that reduced expression of SLC25A3 in fatty liver contributes to electron leak from mitochondria by limiting Cu availability, rendering hepatocytes more susceptible to oxidative stress. This study provides evidence that SLC25A3 is a novel risk factor for developing NASH.

Keywords:  Copper transport; Fatty acid metabolism; Lipid; Liver injury; Mitochondrial carriers; Mitochondrial membrane potential; Oxidative stress; Phosphate carrier; Redox regulation; SLC25A family

DOI:  https://doi.org/10.1016/j.yexcr.2023.113740
J Cell Biochem. 2023 Aug 11.

The emerging era of lactate: A rising star in cellular signaling and its regulatory mechanisms.

Di Wu, Kejia Zhang, Faheem Ahmed Khan, Qin Wu, Nuruliarizki Shinta Pandupuspitasari, Yuan Tang, Kaifeng Guan, Fei Sun, Chunjie Huang.

  Cellular metabolites are ancient molecules with pleiotropic implications in health and disease. Beyond their cognate roles, they have signaling functions as the ligands for specific receptors and the precursors for epigenetic or posttranslational modifications. Lactate has long been recognized as a metabolic waste and fatigue product mainly produced from glycolytic metabolism. Recent evidence however suggests lactate is an unique molecule with diverse signaling attributes in orchestration of numerous biological processes, including tumor immunity and neuronal survival. The copious metabolic and non-metabolic functions of lactate mediated by its bidirectional shuttle between cells or intracellular organelles lead to a phenotype called "lactormone." Importantly, the mechanisms of lactate signaling, via acting as a molecular sensor and a regulator of NAD+ metabolism and AMP-activated protein kinase signaling, and via the newly identified lactate-driven lactylation, have been discovered. Further, we include a brief discussion about the autocrine regulation of efferocytosis by lactate in Sertoli cells which favoraerobic glycolysis. By emphasizing a repertoire of the most recent discovered mechanisms of lactate signaling, this review will open tantalizing avenues for future investigations cracking the regulatory topology of lactate signaling covered in the veil of mystery.

Keywords:  aerobic glycolysis; efferocytosis; lactate signaling; lactate-driven lactylation; tumor immunity

DOI:  https://doi.org/10.1002/jcb.30458
Int J Mol Sci. 2023 Jul 26. pii: 11969. [Epub ahead of print]24(15):

Glucose Deprivation Induces Cancer Cell Death through Failure of ROS Regulation.

Mingyu Kang, Joon H Kang, In A Sim, Do Y Seong, Suji Han, Hyonchol Jang, Ho Lee, Sang W Kang, Soo-Youl Kim.

  In previous work, we showed that cancer cells do not depend on glycolysis for ATP production, but they do on fatty acid oxidation. However, we found some cancer cells induced cell death after glucose deprivation along with a decrease of ATP production. We investigated the different response of glucose deprivation with two types of cancer cells including glucose insensitive cancer cells (GIC) which do not change ATP levels, and glucose sensitive cancer cells (GSC) which decrease ATP production in 24 h. Glucose deprivation-induced cell death in GSC by more than twofold after 12 h and by up to tenfold after 24 h accompanied by decreased ATP production to compare to the control (cultured in glucose). Glucose deprivation decreased the levels of metabolic intermediates of the pentose phosphate pathway (PPP) and the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) in both GSC and GIC. However, glucose deprivation increased reactive oxygen species (ROS) only in GSC, suggesting that GIC have a higher tolerance for decreased NADPH than GSC. The twofold higher ratio of reduced/oxidized glutathione (GSH/GSSG) in GIS than in GSC correlates closely with the twofold lower ROS levels under glucose starvation conditions. Treatment with N-acetylcysteine (NAC) as a precursor to the biologic antioxidant glutathione restored ATP production by 70% and reversed cell death caused by glucose deprivation in GSC. The present findings suggest that glucose deprivation-induced cancer cell death is not caused by decreased ATP levels, but rather triggered by a failure of ROS regulation by the antioxidant system. Conclusion is clear that glucose deprivation-induced cell death is independent from ATP depletion-induced cell death.

Keywords:  ROS; cancer metabolism; cell death; glucose deprivation; glycolysis

DOI:  https://doi.org/10.3390/ijms241511969
Int J Mol Sci. 2023 Aug 06. pii: 12486. [Epub ahead of print]24(15):

Exploring Molecular Targets for Mitochondrial Therapies in Neurodegenerative Diseases.

Germán Plascencia-Villa, George Perry.

  The progressive deterioration of function and structure of brain cells in neurodegenerative diseases is accompanied by mitochondrial dysfunction, affecting cellular metabolism, intracellular signaling, cell differentiation, morphogenesis, and the activation of programmed cell death. However, most of the efforts to develop therapies for Alzheimer's and Parkinson's disease have focused on restoring or maintaining the neurotransmitters in affected neurons, removing abnormal protein aggregates through immunotherapies, or simply treating symptomatology. However, none of these approaches to treating neurodegeneration can stop or reverse the disease other than by helping to maintain mental function and manage behavioral symptoms. Here, we discuss alternative molecular targets for neurodegeneration treatments that focus on mitochondrial functions, including regulation of calcium ion (Ca2+) transport, protein modification, regulation of glucose metabolism, antioxidants, metal chelators, vitamin supplementation, and mitochondrial transference to compromised neurons. After pre-clinical evaluation and studies in animal models, some of these therapeutic compounds have advanced to clinical trials and are expected to have positive outcomes in subjects with neurodegeneration. These mitochondria-targeted therapeutic agents are an alternative to established or conventional molecular targets that have shown limited effectiveness in treating neurodegenerative diseases.

Keywords:  Alzheimer’s disease; Parkinson’s disease; mitochondria; mitochondrial dysfunction; neurodegeneration; neurons; oxidative stress

DOI:  https://doi.org/10.3390/ijms241512486
Redox Biol. 2023 Aug 06. pii: S2213-2317(23)00242-2. [Epub ahead of print]65 102841

Glutathionylation of pyruvate dehydrogenase complex E2 and inflammatory cytokine production during acute inflammation are magnified by mitochondrial oxidative stress.

David L Long, Charles E McCall, Leslie B Poole.

  Lipopolysaccharide (LPS) is a known inducer of inflammatory signaling which triggers generation of reactive oxygen species (ROS) and cell death in responsive cells like THP-1 promonocytes and freshly isolated human monocytes. A key LPS-responsive metabolic pivot point is the 9 MDa mitochondrial pyruvate dehydrogenase complex (PDC), which provides pyruvate dehydrogenase (E1), lipoamide-linked transacetylase (E2) and lipoamide dehydrogenase (E3) activities to produce acetyl-CoA from pyruvate. While phosphorylation-dependent decreases in PDC activity following LPS treatment or sepsis have been deeply investigated, redox-linked processes have received less attention. Data presented here demonstrate that LPS-induced reversible oxidation within PDC occurs in PDCE2 in both THP-1 cells and primary human monocytes. Knockout of PDCE2 by CRISPR and expression of FLAG-tagged PDCE2 in THP-1 cells demonstrated that LPS-induced glutathionylation is associated with wild type PDCE2 but not mutant protein lacking the lipoamide-linking lysine residues. Moreover, the mitochondrially-targeted electrophile MitoCDNB, which impairs both glutathione- and thioredoxin-based reductase systems, elevates ROS similar to LPS but does not cause PDCE2 glutathionylation. However, LPS and MitoCDNB together are highly synergistic for PDCE2 glutathionylation, ROS production, and cell death. Surprisingly, the two treatments together had differential effects on cytokine production; pro-inflammatory IL-1β production was enhanced by the co-treatment, while IL-10, an important anti-inflammatory cytokine, dropped precipitously compared to LPS treatment alone. This new information may expand opportunities to understand and modulate PDC redox status and activity and improve the outcomes of pathological inflammation.

Keywords:  Glutathionylation; Inflammation; Lipoamide; Pyruvate dehydrogenase complex; Sepsis

DOI:  https://doi.org/10.1016/j.redox.2023.102841
Mol Cell Endocrinol. 2023 Aug 09. pii: S0303-7207(23)00190-9. [Epub ahead of print] 112039

AMPD2 plays important roles in regulating hepatic glucose and lipid metabolism.

Haiyan Yang, Qiang Wang, Yuemei Xi, Wei Yu, De Xie, Hiroko Morisaki, Takayuki Morisaki, Jidong Cheng.

  Dysregulation of hepatic glucose and lipid metabolism can instigate the onset of various metabolic disorders including obesity, dyslipidemia, insulin resistance, type 2 diabetes, and fatty liver disease. Adenosine monophosphate (AMP) deaminase (AMPD), which converts AMP to inosine monophosphate, plays a key role in maintaining adenylate energy charge. AMPD2 is the major isoform present in the liver. However, the mechanistic link between AMPD2 and hepatic glucose and lipid metabolism remains elusive. In this study, we probed into the hepatic glucose and lipid metabolism in AMPD2-deficient (A2-/-) mice. These mice exhibited reduced body weight, fat accumulation, and blood glucose levels, coupled with enhanced insulin sensitivity while maintaining consistent calorie intake and spontaneous motor activity compared with wild type mice. Furthermore, A2-/- mice showed mitigated obesity and hyper-insulinemia induced by high-fat diet (HFD) but elevated levels of the serum triglyceride and cholesterol. The hepatic mRNA levels of several fatty acid and cholesterol metabolism-related genes were altered in A2-/- mice. RNA sequencing unveiled multiple alterations in lipid metabolic pathways due to AMPD2 deficiency. These mice were also more susceptible to fasting or HFD-induced hepatic lipid accumulation. The liver exhibited elevated AMP levels but unaltered AMP/ATP ratio. In addition, AMPD2 deficiency is not associated with the adenosine production. In summary, this study established a link between purine metabolism and hepatic glucose and lipid metabolism via AMPD2, providing novel insights into these metabolic pathways.

Keywords:  AMPD2 deficiency; Glucose metabolism; Insulin sensitivity; Lipid metabolism

DOI:  https://doi.org/10.1016/j.mce.2023.112039
JCI Insight. 2023 Aug 10. pii: e160987. [Epub ahead of print]

ACOT1 deficiency attenuates high-fat diet induced fat mass gain by increasing energy expenditure.

Timothy D Heden, Mallory P Franklin, Christina Dailey, Mara T Mashek, Chen Chen, Douglas G Mashek.

  Acyl-CoA thioesterase 1 (ACOT1) catalyzes the hydrolysis of long-chain acyl-CoAs to free fatty acids and coenzyme A and is typically upregulated in obesity. Whether targeting ACOT1 in the setting of high-fat diet induced obesity would be metabolically beneficial is not known. Here we report that male and female ACOT1KO mice are partially protected from high-fat diet induced obesity, an effect associated with increased energy expenditure without alterations in physical activity or food intake. In males, ACOT1 deficiency increased mitochondrial uncoupling protein-2 (UCP2) protein abundance, while reducing 4-hydroxynonenal (4-HNE), a marker of oxidative stress, in white adipose tissue and liver of high-fat fed mice. Moreover, concurrent knockdown of UCP2 with ACOT1 in hepatocytes prevented increases in oxygen consumption observed with ACOT1 knockdown during high lipid loading, suggesting that UCP2-induced uncoupling may increase energy expenditure to attenuate weight gain. Together, these data indicate that targeting ACOT1 may be effective for obesity prevention during caloric excess by increasing energy expenditure.

Keywords:  Fatty acid oxidation; Metabolism; Obesity; Uncoupling proteins

DOI:  https://doi.org/10.1172/jci.insight.160987
Exp Physiol. 2023 Aug 11.

Loss and recovery of myocardial mitochondria in mice under different tail suspension time: Apoptosis and mitochondrial fission, fusion and autophagy.

Zhe Wang, Xing-Chen Wang, Ya-Fei Chen, Chuan-Li Wang, Le Chen, Ming-Yue Jiang, Xi-Wei Liu, Xiao-Xuan Zhang, Yong-Zhen Feng, Jin-Hui Xu.

  Long-term weightlessness in animals can cause changes in myocardial structure and function, in which mitochondria play an important role. Here, a tail suspension (TS) Kunming mouse (Mus musculus) model was used to simulate the effects of weightlessness on the heart. We investigated the effects of 2 and 4 weeks of TS (TS2 and TS4) on myocardial mitochondrial ultrastructure and oxidative respiratory function and on the molecular mechanisms of apoptosis and mitochondrial fission, autophagy and fusion-related signalling. Our study revealed significant changes in the ultrastructural features of cardiomyocytes in response to TS. The results showed: (1) mitochondrial swelling and disruption of cristae in TS2, but mitochondrial recovery and denser cristae in TS4; (2) an increase in the total number of mitochondria and number of sub-mitochondria in TS4; (3) no significant changes in the nuclear ultrastructure or DNA fragmentation among the two TS groups and the control group; (4) an increase in the bax/bcl-2 protein levels in the two TS groups, indicating increased activation of the bax-mediated apoptosis pathway; (5) no change in the phosphorylation ratio of dynamin-related protein 1 in the two TS groups; (6) an increase in the protein levels of optic atrophy 1 and mitofusin 2 in the two TS groups; and (7) in comparison to the TS2 group, an increase in the phosphorylation ratio of parkin and the ratio of LC3II to LC3I in TS4, suggesting an increase in autophagy. Taken together, these findings suggest that mitochondrial autophagy and fusion levels increased after 4 weeks of TS, leading to a restoration of the bax-mediated myocardial apoptosis pathway observed after 2 weeks of TS. NEW FINDINGS: What is the central question of this study? What are the effects of 2 and 4 weeks of tail suspension on myocardial mitochondrial ultrastructure and oxidative respiratory function and on the molecular mechanisms of apoptosis and mitochondrial fission, autophagy and fusion-related signalling? What is the main finding and its importance? Increased mitochondrial autophagy and fusion levels after 4 weeks of tail suspension help to reshape the morphology and increase the number of myocardial mitochondria.

Keywords:  apoptosis; heart; microgravity; mitochondria

DOI:  https://doi.org/10.1113/EP090518
Sci Adv. 2023 Aug 09. 9(32): eadf7119

TNIK is a conserved regulator of glucose and lipid metabolism in obesity.

T C Phung Pham, Lucile Dollet, Mona S Ali, Steffen H Raun, Lisbeth L V Møller, Abbas Jafari, Nicholas Ditzel, Nicoline R Andersen, Andreas M Fritzen, Zachary Gerhart-Hines, Bente Kiens, Anu Suomalainen, Stephen J Simpson, Morten Salling Olsen, Arnd Kieser, Peter Schjerling, Anni I Nieminen, Erik A Richter, Essi Havula, Lykke Sylow.

Obesity and type 2 diabetes (T2D) are growing health challenges with unmet treatment needs. Traf2- and NCK-interacting protein kinase (TNIK) is a recently identified obesity- and T2D-associated gene with unknown functions. We show that TNIK governs lipid and glucose homeostasis in Drosophila and mice. Loss of the Drosophila ortholog of TNIK, misshapen, altered the metabolite profiles and impaired de novo lipogenesis in high sugar-fed larvae. Tnik knockout mice exhibited hyperlocomotor activity and were protected against diet-induced fat expansion, insulin resistance, and hepatic steatosis. The improved lipid profile of Tnik knockout mice was accompanied by enhanced skeletal muscle and adipose tissue insulin-stimulated glucose uptake and glucose and lipid handling. Using the T2D Knowledge Portal and the UK Biobank, we observed associations of TNIK variants with blood glucose, HbA1c, body mass index, body fat percentage, and feeding behavior. These results define an untapped paradigm of TNIK-controlled glucose and lipid metabolism.

DOI: https://doi.org/10.1126/sciadv.adf7119
Int J Mol Sci. 2023 Aug 01. pii: 12315. [Epub ahead of print]24(15):

The Role of Intracellular Ca2+ and Mitochondrial ROS in Small Aβ1-42 Oligomer-Induced Microglial Death.

Aiste Jekabsone, Silvija Jankeviciute, Katryna Pampuscenko, Vilmante Borutaite, Ramune Morkuniene.

  Alzheimer's disease (AD) is the most common form of dementia worldwide, and it contributes up to 70% of cases. AD pathology involves abnormal amyloid beta (Aβ) accumulation, and the link between the Aβ1-42 structure and toxicity is of major interest. NMDA receptors (NMDAR) are thought to be essential in Aβ-affected neurons, but the role of this receptor in glial impairment is still unclear. In addition, there is insufficient knowledge about the role of Aβ species regarding mitochondrial redox states in neurons and glial cells, which may be critical in developing Aβ-caused neurotoxicity. In this study, we investigated whether different Aβ1-42 species-small oligomers, large oligomers, insoluble fibrils, and monomers-were capable of producing neurotoxic effects via microglial NMDAR activation and changes in mitochondrial redox states in primary rat brain cell cultures. Small Aβ1-42 oligomers induced a concentration- and time-dependent increase in intracellular Ca2+ and necrotic microglial death. These changes were partially prevented by the NMDAR inhibitors MK801, memantine, and D-2-amino-5-phosphopentanoic acid (DAP5). Neither microglial intracellular Ca2+ nor viability was significantly affected by larger Aβ1-42 species or monomers. In addition, the small Aβ1-42 oligomers caused mitochondrial reactive oxygen species (mtROS)-mediated mitochondrial depolarization, glutamate release, and neuronal cell death. In microglia, the Aβ1-42-induced mtROS overproduction was mediated by intracellular calcium ions and Aβ-binding alcohol dehydrogenase (ABAD). The data suggest that the pharmacological targeting of microglial NMDAR and mtROS may be a promising strategy for AD therapy.

Keywords:  Alzheimer’s disease; NMDA receptors; amyloid-β; cell death; glutamate; microglia; mitochondrial ROS

DOI:  https://doi.org/10.3390/ijms241512315
Int J Mol Sci. 2023 Aug 06. pii: 12485. [Epub ahead of print]24(15):

Alterations in Mitochondrial Morphology and Quality Control in Primary Mouse Lung Microvascular Endothelial Cells and Human Dermal Fibroblasts under Hyperglycemic Conditions.

Natalia V Belosludtseva, Dmitriy A Serov, Vlada S Starinets, Nikita V Penkov, Konstantin N Belosludtsev.

  The effect of hyperglycemia on the morphology of individual mitochondria and the state of the mitochondrial network in primary mouse lung microvascular endotheliocytes and human dermal fibroblasts has been investigated. The cells were exposed to high (30 mM) and low (5.5 mM) glucose concentrations for 36 h. In primary endotheliocytes, hyperglycemic stress induced a significant increase in the number of mitochondria and a decrease in the interconnectivity value of the mitochondrial network, which was associated with a decrease in the mean size of the mitochondria. Analysis of the mRNA level of the genes of proteins responsible for mitochondrial biogenesis and mitophagy revealed an increase in the expression level of the Ppargc1a, Pink1, and Parkin genes, indicating stimulated mitochondrial turnover in endotheliocytes under high glucose conditions. In primary fibroblasts, hyperglycemia caused a decrease in the number of mitochondria and an increase in their size. As a result, the mitochondria exhibited higher values for elongation. In parallel, the mRNA level of the Ppargc1a and Mfn2 genes in fibroblasts exposed to hyperglycemia was reduced. These findings indicate that high glucose concentrations induced cell-specific morphological rearrangements of individual mitochondria and the mitochondrial network, which may be relevant during mitochondria-targeted drug testing and therapy for hyperglycemic and diabetic conditions.

Keywords:  diabetic hyperglycemia; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial morphology; mitophagy

DOI:  https://doi.org/10.3390/ijms241512485
Brain Behav Immun. 2023 Aug 03. pii: S0889-1591(23)00223-4. [Epub ahead of print]113 328-339

A novel role for astrocytic fragmented mitochondria in regulating morphine addiction.

Jie Rao, Weikang Sun, Xinran Wang, Jin Li, Zhichun Zhang, Feifan Zhou.

  Chronic morphine exposure causes the development of addictive behaviors, accompanied by an increase in neuroinflammation in the central nervous system. While previous researches have shown that astrocytes contribute to brain diseases, the role of astrocyte in morphine addiction through induced neuroinflammation remain unexplored. Here we show that morphine-induced inflammation requires the crosstalk among neuron, astrocyte, and microglia. Specifically, astrocytes respond to morphine-induced neuronal activation by increasing glycolytic metabolism. The dysregulation of glycolysis leads to an increased in the generation of mitochondrial reactive oxygen species and causes excessive mitochondrial fragmentation in astrocytes. These fragmented, dysfunctional mitochondria are consequently released into extracellular environment, leading to activation of microglia and release of inflammatory cytokines. We also found that blocking the nicotinamide adenine dinucleotide salvage pathway with FK866 could inhibit astrocytic glycolysis and restore the mitochondrial homeostasis and effectively attenuate neuroinflammatory responses. Importantly, FK866 reversed morphine-induced addictive behaviors in mice. In summary, our findings illustrate an essential role of astrocytic immunometabolism in morphine induced neural and behavioral plasticity, providing a novel insight into the interactions between neurons, astrocytes, and microglia in the brain affected by chronic morphine exposure.

Keywords:  Astrocyte; Glycolysis; Mitochondrial fragmentation; Morphine addiction

DOI:  https://doi.org/10.1016/j.bbi.2023.07.030