bims-celmim 2024-01-14 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2024–01–14
28 papers selected by
Marc Segarra Mondejar, University of Cologne

Accessory subunit NDUFB4 participates in mitochondrial complex I supercomplex formation.
Glycolytic enzymes in non-glycolytic web: functional analysis of the key players.
Protein lysine acetylation does not contribute to the high rates of fatty acid oxidation seen in the post-ischemic heart.
Effects of aging on glucose and lipid metabolism in mice.
TALK-1-mediated alterations of β-cell mitochondrial function and insulin secretion impair glucose homeostasis on a diabetogenic diet.
Local and dynamic regulation of neuronal glycolysis in vivo.
Unexpected roles for AMPK in suppression of autophagy and reactivation of mTORC1 signaling during prolonged amino acid deprivation.
Systems-level analyses dissociate genetic regulators of reactive oxygen species and energy production.
Upregulated pexophagy limits the capacity of selective autophagy.
Control of NAD+ homeostasis by autophagic flux modulates mitochondrial and cardiac function.
Post-translational modulation of cell signalling through protein succinylation.
Energy depletion by cell proliferation sensitizes the kidney epithelial cells to injury.
Immunosurveillance encounters cancer metabolism.
CGI1746 targets σ1R to modulate ferroptosis through mitochondria-associated membranes.
Mediators of necroptosis: from cell death to metabolic regulation.
Pyruvate dehydrogenase kinase regulates macrophage polarization in metabolic and inflammatory diseases.
Multi-omics analysis reveals GAPDH posttranscriptional regulation of IFN-γ and PHGDH as a metabolic checkpoint of microglia polarization.
Brain energy metabolism: A roadmap for future research.
Renal Mitochondrial ATP Transporter Ablation Ameliorates Obesity-Induced Chronic Kidney Disease.
DMT1-dependent endosome-mitochondria interactions regulate mitochondrial iron translocation and metastatic outgrowth.
Neuronal Autophagy: Regulations and Implications in Health and Disease.
Metabolomics profiling reveals distinct, sex-specific signatures in the serum and brain metabolomes in the mouse models of Alzheimer's disease.
Radiation-induced changes in energy metabolism result in mitochondrial dysfunction in salivary glands.
Recreating metabolic interactions of the tumour microenvironment.
Cristae shaping and dynamics in mitochondrial function.
O-GlcNAc regulates the mitochondrial integrated stress response by regulating ATF4.
Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis.
Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.

J Biol Chem. 2024 Jan 08. pii: S0021-9258(24)00002-4. [Epub ahead of print] 105626

Accessory subunit NDUFB4 participates in mitochondrial complex I supercomplex formation.

Gaganvir Parmar, Claire Fong-McMaster, Chantal Pileggi, David A Patten, Alexanne Cuillerier, Stephanie Myers, Ying Wang, Siegfried Hekimi, Miroslava Cuperlovic-Culf, Mary-Ellen Harper.

  Mitochondrial electron transport chain (ETC) complexes organize into supramolecular structures called respiratory supercomplexes (SCs). The role of respiratory SC remains largely unconfirmed despite evidence supporting their necessity for mitochondrial respiratory function. The mechanisms underlying the formation of the I1III2IV1 "respirasome" SC are also not fully understood, further limiting insights into these processes in physiology and diseases, including neurodegeneration and metabolic syndromes. NDUFB4 is a complex I accessory subunit that contains residues that interact with the subunit UQCRC1 from complex III, suggesting that NDUFB4 is integral for I1III2IV1 respirasome integrity. Here, we introduced specific point mutations to Asn24 (N24) and Arg30 (R30) residues on NDUFB4 to decipher the role of I1III2-containing respiratory SCs in cellular metabolism while minimizing the functional consequences to complex I assembly. Our results demonstrate that NDUFB4 point mutations N24A and R30A impair I1III2IV1 respirasome assembly and reduce mitochondrial respiratory flux. Steady-state metabolomics also revealed a global decrease in TCA cycle metabolites, affecting NADH-generating substrates. Taken together, our findings highlight an integral role of NDUFB4 in respirasome assembly and demonstrate the functional significance of SCs in regulating mammalian cell bioenergetics.

Keywords:  Mitochondria; NDUFB4; electron transport chain; oxidative phosphorylation; respirasome; steady-state metabolomics; supercomplexes

DOI:  https://doi.org/10.1016/j.jbc.2024.105626
Cell Biochem Biophys. 2024 Jan 09.

Glycolytic enzymes in non-glycolytic web: functional analysis of the key players.

Avirup Malla, Suvroma Gupta, Runa Sur.

  To survive in the tumour microenvironment, cancer cells undergo rapid metabolic reprograming and adaptability. One of the key characteristics of cancer is increased glycolytic selectivity and decreased oxidative phosphorylation (OXPHOS). Apart from ATP synthesis, glycolysis is also responsible for NADH regeneration and macromolecular biosynthesis, such as amino acid biosynthesis and nucleotide biosynthesis. This allows cancer cells to survive and proliferate even in low-nutrient and oxygen conditions, making glycolytic enzymes a promising target for various anti-cancer agents. Oncogenic activation is also caused by the uncontrolled production and activity of glycolytic enzymes. Nevertheless, in addition to conventional glycolytic processes, some glycolytic enzymes are involved in non-canonical functions such as transcriptional regulation, autophagy, epigenetic changes, inflammation, various signaling cascades, redox regulation, oxidative stress, obesity and fatty acid metabolism, diabetes and neurodegenerative disorders, and hypoxia. The mechanisms underlying the non-canonical glycolytic enzyme activities are still not comprehensive. This review summarizes the current findings on the mechanisms fundamental to the non-glycolytic actions of glycolytic enzymes and their intermediates in maintaining the tumor microenvironment.

Keywords:  Cancer; Enzyme; Glycolysis; Metabolism; Non-glycolytic function; OXPHOS

DOI:  https://doi.org/10.1007/s12013-023-01213-5
Sci Rep. 2024 Jan 12. 14(1): 1193

Protein lysine acetylation does not contribute to the high rates of fatty acid oxidation seen in the post-ischemic heart.

Ezra B Ketema, Muhammad Ahsan, Liyan Zhang, Qutuba G Karwi, Gary D Lopaschuk.

High rates of cardiac fatty acid oxidation during reperfusion of ischemic hearts contribute to contractile dysfunction. This study aimed to investigate whether lysine acetylation affects fatty acid oxidation rates and recovery in post-ischemic hearts. Isolated working hearts from Sprague Dawley rats were perfused with 1.2 mM palmitate and 5 mM glucose and subjected to 30 min of ischemia and 40 min of reperfusion. Cardiac function, fatty acid oxidation, glucose oxidation, and glycolysis rates were compared between pre- and post-ischemic hearts. The acetylation status of enzymes involved in cardiac energy metabolism was assessed in both groups. Reperfusion after ischemia resulted in only a 41% recovery of cardiac work. Fatty acid oxidation and glycolysis rates increased while glucose oxidation rates decreased. The contribution of fatty acid oxidation to ATP production and TCA cycle activity increased from 90 to 93% and from 94.9 to 98.3%, respectively, in post-ischemic hearts. However, the overall acetylation status and acetylation levels of metabolic enzymes did not change in response to ischemia and reperfusion. These findings suggest that acetylation may not contribute to the high rates of fatty acid oxidation and reduced glucose oxidation observed in post-ischemic hearts perfused with high levels of palmitate substrate.

DOI: https://doi.org/10.1038/s41598-024-51571-0
bioRxiv. 2023 Dec 18. pii: 2023.12.17.572088. [Epub ahead of print]

Effects of aging on glucose and lipid metabolism in mice.

Evan C Lien, Ngoc Vu, Anna M Westermark, Laura V Danai, Allison N Lau, Yetiş Gültekin, Matthew A Kukurugya, Bryson D Bennett, Matthew G Vander Heiden.

Aging is accompanied by multiple molecular changes that contribute to aging-associated pathologies, such as accumulation of cellular damage and mitochondrial dysfunction. Tissue metabolism can also change with age, in part because mitochondria are central to cellular metabolism. Moreover, the co-factor NAD+, which is reported to decline across multiple tissue types during aging, plays a central role in metabolic pathways such as glycolysis, the tricarboxylic acid cycle, and the oxidative synthesis of nucleotides, amino acids, and lipids. To further characterize how tissue metabolism changes with age, we intravenously infused [U-13C]-glucose into young and old C57BL/6J, WSB/EiJ, and Diversity Outbred mice to trace glucose fate into downstream metabolites within plasma, liver, gastrocnemius muscle, and brain tissues. We found that glucose incorporation into central carbon and amino acid metabolism was robust during healthy aging across these different strains of mice. We also observed that levels of NAD+, NADH, and the NAD+/NADH ratio were unchanged in these tissues with healthy aging. However, aging tissues, particularly brain, exhibited evidence of up-regulated fatty acid and sphingolipid metabolism reactions that regenerate NAD+ from NADH. Because mitochondrial respiration, a major source of NAD+ regeneration, is reported to decline with age, our data supports a model where NAD+-generating lipid metabolism reactions may buffer against changes in NAD+/NADH during healthy aging.

DOI: https://doi.org/10.1101/2023.12.17.572088
Cell Rep. 2024 Jan 10. pii: S2211-1247(24)00001-9. [Epub ahead of print]43(1): 113673

TALK-1-mediated alterations of β-cell mitochondrial function and insulin secretion impair glucose homeostasis on a diabetogenic diet.

Sarah M Graff, Arya Y Nakhe, Prasanna K Dadi, Matthew T Dickerson, Jordyn R Dobson, Karolina E Zaborska, Chloe E Ibsen, Regan B Butterworth, Nicholas C Vierra, David A Jacobson.

  Mitochondrial Ca2+ ([Ca2+]m) homeostasis is critical for β-cell function and becomes disrupted during the pathogenesis of diabetes. [Ca2+]m uptake is dependent on elevations in cytoplasmic Ca2+ ([Ca2+]c) and endoplasmic reticulum Ca2+ ([Ca2+]ER) release, both of which are regulated by the two-pore domain K+ channel TALK-1. Here, utilizing a novel β-cell TALK-1-knockout (β-TALK-1-KO) mouse model, we found that TALK-1 limited β-cell [Ca2+]m accumulation and ATP production. However, following exposure to a high-fat diet (HFD), ATP-linked respiration, glucose-stimulated oxygen consumption rate, and glucose-stimulated insulin secretion (GSIS) were increased in control but not TALK1-KO mice. Although β-TALK-1-KO animals showed similar GSIS before and after HFD treatment, these mice were protected from HFD-induced glucose intolerance. Collectively, these data identify that TALK-1 channel control of β-cell function reduces [Ca2+]m and suggest that metabolic remodeling in diabetes drives dysglycemia.

Keywords:  CP: Cell biology; CP: Metabolism; K2P; TALK-1; calcium handling; diabetes; endoplasmic reticulum; insulin secretion; metabolism; mitochondria; pancreatic β-cell; two-pore-domain potassium channel

DOI:  https://doi.org/10.1016/j.celrep.2024.113673
Proc Natl Acad Sci U S A. 2024 Jan 16. 121(3): e2314699121

Local and dynamic regulation of neuronal glycolysis in vivo.

Aaron D Wolfe, John N Koberstein, Chadwick B Smith, Melissa L Stewart, Ian J Gonzalez, Marc Hammarlund, Anthony A Hyman, Philip J S Stork, Richard H Goodman, Daniel A Colón-Ramos.

  Energy metabolism supports neuronal function. While it is well established that changes in energy metabolism underpin brain plasticity and function, less is known about how individual neurons modulate their metabolic states to meet varying energy demands. This is because most approaches used to examine metabolism in living organisms lack the resolution to visualize energy metabolism within individual circuits, cells, or subcellular regions. Here, we adapted a biosensor for glycolysis, HYlight, for use in Caenorhabditis elegans to image dynamic changes in glycolysis within individual neurons and in vivo. We determined that neurons cell-autonomously perform glycolysis and modulate glycolytic states upon energy stress. By examining glycolysis in specific neurons, we documented a neuronal energy landscape comprising three general observations: 1) glycolytic states in neurons are diverse across individual cell types; 2) for a given condition, glycolytic states within individual neurons are reproducible across animals; and 3) for varying conditions of energy stress, glycolytic states are plastic and adapt to energy demands. Through genetic analyses, we uncovered roles for regulatory enzymes and mitochondrial localization in the cellular and subcellular dynamic regulation of glycolysis. Our study demonstrates the use of a single-cell glycolytic biosensor to examine how energy metabolism is distributed across cells and coupled to dynamic states of neuronal function and uncovers unique relationships between neuronal identities and metabolic landscapes in vivo.

Keywords:  C. elegans; biosensor; energy metabolism; glycolysis; neurons

DOI:  https://doi.org/10.1073/pnas.2314699121
bioRxiv. 2023 Dec 21. pii: 2023.12.20.572593. [Epub ahead of print]

Unexpected roles for AMPK in suppression of autophagy and reactivation of mTORC1 signaling during prolonged amino acid deprivation.

Dubek Kazyken, Sydney G Dame, Claudia Wang, Maxwell Wadley, Diane C Fingar.

Amino acid withdrawal suppresses mTORC1 signaling rapidly, which initiates macroautophagy (herein, autophagy). Prolonged amino acid deprivation, however, leads to partial reactivation of mTORC1 due to the liberation of free amino acids by autophagic proteolysis. We observed impaired reactivation of mTORC1 signaling and increased apoptotic cell death upon prolonged amino acid withdrawal in cells lacking the AMPKα1/α2 catalytic subunits. These findings align well with the role of AMPK in promoting cell survival during energetic stress but oppose the well-documented inhibitory action of AMPK toward mTORC1. AMPK-mediated reactivation of mTORC1 during prolonged amino acid deprivation could be explained, however, if AMPK were required for autophagy. Indeed, a prevailing view posits that activation of AMPK by glucose withdrawal promotes autophagy and mitophagy through multisite phosphorylation of ULK1. When we examined the role of AMPK in autophagy induced by amino acid deprivation, however, we found unexpectedly that autophagy remained unimpaired in cells lacking AMPK α1/α2, as monitored by several autophagic readouts in several cell lines. Moreover, the absence of AMPK increased ULK1 signaling, LC3b lipidation, and lysosomal acidity, and the phosphorylation of ULK1 S555 (an AMPK site proposed to induce autophagy) decreased upon amino acid withdrawal or pharmacological mTORC1 inhibition. In addition, activation of AMPK with compound 991, glucose deprivation, or AICAR blunted basal and amino acid withdrawal-induced autophagy. Together our results demonstrate that AMPK suppresses rather than promotes autophagy and supports mTORC1 signaling during prolonged amino acid deprivation, revealing unexpected roles for AMPK in control of these processes.

DOI: https://doi.org/10.1101/2023.12.20.572593
Proc Natl Acad Sci U S A. 2024 Jan 16. 121(3): e2307904121

Systems-level analyses dissociate genetic regulators of reactive oxygen species and energy production.

Neal K Bennett, Megan Lee, Adam L Orr, Ken Nakamura.

  Respiratory chain dysfunction can decrease ATP and increase reactive oxygen species (ROS) levels. Despite the importance of these metabolic parameters to a wide range of cellular functions and disease, we lack an integrated understanding of how they are differentially regulated. To address this question, we adapted a CRISPRi- and FACS-based platform to compare the effects of respiratory gene knockdown on ROS to their effects on ATP. Focusing on genes whose knockdown is known to decrease mitochondria-derived ATP, we showed that knockdown of genes in specific respiratory chain complexes (I, III, and CoQ10 biosynthesis) increased ROS, whereas knockdown of other low ATP hits either had no impact (mitochondrial ribosomal proteins) or actually decreased ROS (complex IV). Moreover, although shifting metabolic conditions profoundly altered mitochondria-derived ATP levels, it had little impact on mitochondrial or cytosolic ROS. In addition, knockdown of a subset of complex I subunits-including NDUFA8, NDUFB4, and NDUFS8-decreased complex I activity, mitochondria-derived ATP, and supercomplex level, but knockdown of these genes had differential effects on ROS. Conversely, we found an essential role for ether lipids in the dynamic regulation of mitochondrial ROS levels independent of ATP. Thus, our results identify specific metabolic regulators of cellular ATP and ROS balance that may help dissect the roles of these processes in disease and identify therapeutic strategies to independently target energy failure and oxidative stress.

Keywords:  ATP; CRISPRi; ROS; metabolism; mitochondria

DOI:  https://doi.org/10.1073/pnas.2307904121
Nat Commun. 2024 Jan 09. 15(1): 375

Upregulated pexophagy limits the capacity of selective autophagy.

Kyla Germain, Raphaella W L So, Laura F DiGiovanni, Joel C Watts, Robert H J Bandsma, Peter K Kim.

Selective autophagy is an essential process to maintain cellular homeostasis through the constant recycling of damaged or superfluous components. Over a dozen selective autophagy pathways mediate the degradation of diverse cellular substrates, but whether these pathways can influence one another remains unknown. We address this question using pexophagy, the autophagic degradation of peroxisomes, as a model. We show in cells that upregulated pexophagy impairs the selective autophagy of both mitochondria and protein aggregates by exhausting the autophagy initiation factor, ULK1. We confirm this finding in cell models of the pexophagy-mediated form of Zellweger Spectrum Disorder, a disease characterized by peroxisome dysfunction. Further, we extend the generalizability of limited selective autophagy by determining that increased protein aggregate degradation reciprocally reduces pexophagy using cell models of Parkinson's Disease and Huntington's Disease. Our findings suggest that the degradative capacity of selective autophagy can become limited by an increase in one substrate.

DOI: https://doi.org/10.1038/s41467-023-44005-4
EMBO J. 2024 Jan 11.

Control of NAD+ homeostasis by autophagic flux modulates mitochondrial and cardiac function.

Quanjiang Zhang, Zhonggang Li, Qiuxia Li, Samuel Aj Trammell, Mark S Schmidt, Karla Maria Pires, Jinjin Cai, Yuan Zhang, Helena Kenny, Sihem Boudina, Charles Brenner, E Dale Abel.

  Impaired autophagy is known to cause mitochondrial dysfunction and heart failure, in part due to altered mitophagy and protein quality control. However, whether additional mechanisms are involved in the development of mitochondrial dysfunction and heart failure in the setting of deficient autophagic flux remains poorly explored. Here, we show that impaired autophagic flux reduces nicotinamide adenine dinucleotide (NAD+) availability in cardiomyocytes. NAD+ deficiency upon autophagic impairment is attributable to the induction of nicotinamide N-methyltransferase (NNMT), which methylates the NAD+ precursor nicotinamide (NAM) to generate N-methyl-nicotinamide (MeNAM). The administration of nicotinamide mononucleotide (NMN) or inhibition of NNMT activity in autophagy-deficient hearts and cardiomyocytes restores NAD+ levels and ameliorates cardiac and mitochondrial dysfunction. Mechanistically, autophagic inhibition causes the accumulation of SQSTM1, which activates NF-κB signaling and promotes NNMT transcription. In summary, we describe a novel mechanism illustrating how autophagic flux maintains mitochondrial and cardiac function by mediating SQSTM1-NF-κB-NNMT signaling and controlling the cellular levels of NAD+.

Keywords:  Autophagic Flux; Heart Dysfunction; Mitochondrial Homeostasis; NAD+ Metabolism

DOI:  https://doi.org/10.1038/s44318-023-00009-w
Explor Target Antitumor Ther. 2023 ;4(6): 1260-1285

Post-translational modulation of cell signalling through protein succinylation.

Katharina F Kubatzky, Yue Gao, Dayoung Yu.

  Cells need to adapt their activities to extra- and intracellular signalling cues. To translate a received extracellular signal, cells have specific receptors that transmit the signal to downstream proteins so that it can reach the nucleus to initiate or repress gene transcription. Post-translational modifications (PTMs) of proteins are reversible or irreversible chemical modifications that help to further modulate protein activity. The most commonly observed PTMs are the phosphorylation of serine, threonine, and tyrosine residues, followed by acetylation, glycosylation, and amidation. In addition to PTMs that involve the modification of a certain amino acid (phosphorylation, hydrophobic groups for membrane localisation, or chemical groups like acylation), or the conjugation of peptides (SUMOylation, NEDDylation), structural changes such as the formation of disulphide bridge, protein cleavage or splicing can also be classified as PTMs. Recently, it was discovered that metabolites from the tricarboxylic acid (TCA) cycle are not only intermediates that support cellular metabolism but can also modify lysine residues. This has been shown for acetate, succinate, and lactate, among others. Due to the importance of mitochondria for the overall fitness of organisms, the regulatory function of such PTMs is critical for protection from aging, neurodegeneration, or cardiovascular disease. Cancer cells and activated immune cells display a phenotype of accelerated metabolic activity known as the Warburg effect. This metabolic state is characterised by enhanced glycolysis, the use of the pentose phosphate pathway as well as a disruption of the TCA cycle, ultimately causing the accumulation of metabolites like citrate, succinate, and malate. Succinate can then serve as a signalling molecule by directly interacting with proteins, by binding to its G protein-coupled receptor 91 (GPR91) and by post-translationally modifying proteins through succinylation of lysine residues, respectively. This review is focus on the process of protein succinylation and its importance in health and disease.

Keywords:  Succinate; cancer; immune system; lysine succinylation; metabolites; mitochondria; post-translational modifications

DOI:  https://doi.org/10.37349/etat.2023.00196
Am J Physiol Renal Physiol. 2024 Jan 11.

Energy depletion by cell proliferation sensitizes the kidney epithelial cells to injury.

Pierre Galichon, Morgane Lannoy, Li Li, Justine Serre, Sophie Vandermeersch, David Legouis, M Todd Valerius, Juliette Hadchouel, Joseph V Bonventre.

  Acute kidney injury activates both proliferative and anti-proliferative pathways, the consequences of which are not fully elucidated. If an initial proliferation of the renal epithelium is necessary for the successful repair, the persistence of proliferation markers is associated with the occurrence of chronic kidney disease. We hypothesized that proliferation in stress conditions impacts cell viability and renal outcomes. We found that proliferation is associated with cell death after various stresses in kidney cells. In vitro, the ATP/ADP ratio oscillates reproducibly throughout the cell cycle, and cell proliferation is associated with a decreased intracellular ATP/ADP ratio. In vivo, transcriptomic data from transplanted kidneys revealed that proliferation was strongly associated with a decrease in the expression of the mitochondria-encoded genes of the oxidative phosphorylation pathway, but not of the nuclear-encoded ones. These observations suggest that mitochondrial function is a limiting factor for energy production in proliferative kidney cells after injury. The association of increased proliferation and decreased mitochondrial function was indeed associated with poor renal outcomes. In summary, proliferation is an energy demanding process impairing the cellular ability to cope with an injury, highlighting proliferative repair and metabolic recovery as indispensable and interdependent features for successful kidney repair.

Keywords:  acute kidney injury; cell proliferation; cell survival; ichemia repercussion injury; transplantation

DOI:  https://doi.org/10.1152/ajprenal.00023.2023
EMBO Rep. 2024 Jan 12.

Immunosurveillance encounters cancer metabolism.

Yu-Ming Chuang, Sheue-Fen Tzeng, Ping-Chih Ho, Chin-Hsien Tsai.

  Tumor cells reprogram nutrient acquisition and metabolic pathways to meet their energetic, biosynthetic, and redox demands. Similarly, metabolic processes in immune cells support host immunity against cancer and determine differentiation and fate of leukocytes. Thus, metabolic deregulation and imbalance in immune cells within the tumor microenvironment have been reported to drive immune evasion and to compromise therapeutic outcomes. Interestingly, emerging evidence indicates that anti-tumor immunity could modulate tumor heterogeneity, aggressiveness, and metabolic reprogramming, suggesting that immunosurveillance can instruct cancer progression in multiple dimensions. This review summarizes our current understanding of how metabolic crosstalk within tumors affects immunogenicity of tumor cells and promotes cancer progression. Furthermore, we explain how defects in the metabolic cascade can contribute to developing dysfunctional immune responses against cancers and discuss the contribution of immunosurveillance to these defects as a feedback mechanism. Finally, we highlight ongoing clinical trials and new therapeutic strategies targeting cellular metabolism in cancer.

Keywords:  Cancer Evolution; Immunoediting; Immunometabolism

DOI:  https://doi.org/10.1038/s44319-023-00038-w
Nat Chem Biol. 2024 Jan 11.

CGI1746 targets σ1R to modulate ferroptosis through mitochondria-associated membranes.

Zili Zhang, Hong Zhou, Wenjia Gu, Yuehan Wei, Shan Mou, Youjun Wang, Jing Zhang, Qing Zhong.

Ferroptosis is iron-dependent oxidative cell death. Labile iron and polyunsaturated fatty acid (PUFA)-containing lipids are two critical factors for ferroptosis execution. Many processes regulating iron homeostasis and lipid synthesis are critically involved in ferroptosis. However, it remains unclear whether biological processes other than iron homeostasis and lipid synthesis are associated with ferroptosis. Using kinase inhibitor library screening, we discovered a small molecule named CGI1746 that potently blocks ferroptosis. Further studies demonstrate that CGI1746 acts through sigma-1 receptor (σ1R), a chaperone primarily located at mitochondria-associated membranes (MAMs), to inhibit ferroptosis. Suppression of σ1R protects mice from cisplatin-induced acute kidney injury hallmarked by ferroptosis. Mechanistically, CGI1746 treatment or genetic disruption of MAMs leads to defective Ca2+ transfer, mitochondrial reactive oxygen species (ROS) production and PUFA-containing triacylglycerol accumulation. Therefore, we propose a critical role for MAMs in ferroptosis execution.

DOI: https://doi.org/10.1038/s41589-023-01512-1
EMBO Mol Med. 2024 Jan 09.

Mediators of necroptosis: from cell death to metabolic regulation.

Xiaoqin Wu, Laura E Nagy, Jérémie Gautheron.

  Necroptosis, a programmed cell death mechanism distinct from apoptosis, has garnered attention for its role in various pathological conditions. While initially recognized for its involvement in cell death, recent research has revealed that key necroptotic mediators, including receptor-interacting protein kinases (RIPKs) and mixed lineage kinase domain-like protein (MLKL), possess additional functions that go beyond inducing cell demise. These functions encompass influencing critical aspects of metabolic regulation, such as energy metabolism, glucose homeostasis, and lipid metabolism. Dysregulated necroptosis has been implicated in metabolic diseases, including obesity, diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-associated liver disease (ALD), contributing to chronic inflammation and tissue damage. This review provides insight into the multifaceted role of necroptosis, encompassing both cell death and these extra-necroptotic functions, in the context of metabolic diseases. Understanding this intricate interplay is crucial for developing targeted therapeutic strategies in diseases that currently lack effective treatments.

Keywords:  RIP1 Kinase; RIP3 Kinase; MLKL; Cell Death; Metabolism

DOI:  https://doi.org/10.1038/s44321-023-00011-z
Front Immunol. 2023 ;14 1296687

Pyruvate dehydrogenase kinase regulates macrophage polarization in metabolic and inflammatory diseases.

Chenyu Li, Chuanbin Liu, Junfeng Zhang, Yanyu Lu, Bingtong Jiang, Huabao Xiong, Chunxia Li.

  Macrophages are highly heterogeneous and plastic, and have two main polarized phenotypes that are determined by their microenvironment, namely pro- and anti-inflammatory macrophages. Activation of pro-inflammatory macrophages is closely associated with metabolic reprogramming, especially that of aerobic glycolysis. Mitochondrial pyruvate dehydrogenase kinase (PDK) negatively regulates pyruvate dehydrogenase complex activity through reversible phosphorylation and further links glycolysis to the tricarboxylic acid cycle and ATP production. PDK is commonly associated with the metabolism and polarization of macrophages in metabolic and inflammatory diseases. This review examines the relationship between PDK and macrophage metabolism and discusses the mechanisms by which PDK regulates macrophage polarization, migration, and inflammatory cytokine secretion in metabolic and inflammatory diseases. Elucidating the relationships between the metabolism and polarization of macrophages under physiological and pathological conditions, as well as the regulatory pathways involved, may provide valuable insights into the etiology and treatment of macrophage-mediated inflammatory diseases.

Keywords:  inflammation; macrophage; metabolic reprogramming; polarization; pyruvate dehydrogenase kinase

DOI:  https://doi.org/10.3389/fimmu.2023.1296687
Brain Behav Immun. 2024 Jan 10. pii: S0889-1591(24)00006-0. [Epub ahead of print]

Multi-omics analysis reveals GAPDH posttranscriptional regulation of IFN-γ and PHGDH as a metabolic checkpoint of microglia polarization.

Shangchen Yang, Ziqi Yuan, Zhu Yufei, Liang Chensi, Chen Zhenlei, Jie Zhang, Lige Leng.

  A "switch" in the metabolic pattern of microglia is considered to be required to meet the metabolic demands of cell survival and functions. However, how metabolic switches regulate microglial function remains controversial. We found here that exposure to amyloid-β triggers microglial inflammation accompanied by increasing GAPDH levels. The increase of GAPDH, a glycolysis enzyme, leads to the reduced release of interferon-γ (IFN-γ) from inflammatory microglia. Such alternation is translational and is regulated by the binding of glycolysis enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to IFN-γ mRNA. GAPDH, by engaging/disengaging glycolysis and through influencing IFN-γ expression, regulates microglia functions, including phagocytosis and cytokine production. Phosphoglycerate dehydrogenase (PHGDH), screened from different state microglia by metabolomics combined with METARECON analysis, is a metabolic enzyme adjacent downstream of GAPDH and synthesizes serine on the collateral pathway derived from glycolysis. Polarization of microglial with PHGDH as a metabolic checkpoint can be bidirectionally regulated by adding IL-4 or giving PHGDH inhibitors. Therefore, regulation of metabolic enzymes not only reprograms metabolic patterns, but also manipulates microglia functions. Further study should be performed to explore the mechanism of metabolic checkpoints in human microglia or more in vivo animal experiments, and may expand to the effects of various metabolic substrates or enzyme, such as lipids and amino acids, on the functions of microglia.

Keywords:  GAPDH; IFN-γ; Metabolic checkpoint; Microglia; PHGDH; Polarization

DOI:  https://doi.org/10.1016/j.bbi.2024.01.009
J Neurochem. 2024 Jan 06.

Brain energy metabolism: A roadmap for future research.

Caroline D Rae, Joseph A Baur, Karin Borges, Gerald Dienel, Carlos Manlio Díaz-García, Starlette R Douglass, Kelly Drew, João M N Duarte, Jordi Duran, Oliver Kann, Tibor Kristian, Dasfne Lee-Liu, Britta E Lindquist, Ewan C McNay, Michael B Robinson, Douglas L Rothman, Benjamin D Rowlands, Timothy A Ryan, Joseph Scafidi, Susanna Scafidi, C William Shuttleworth, Raymond A Swanson, Gökhan Uruk, Nina Vardjan, Robert Zorec, Mary C McKenna.

  Although we have learned much about how the brain fuels its functions over the last decades, there remains much still to discover in an organ that is so complex. This article lays out major gaps in our knowledge of interrelationships between brain metabolism and brain function, including biochemical, cellular, and subcellular aspects of functional metabolism and its imaging in adult brain, as well as during development, aging, and disease. The focus is on unknowns in metabolism of major brain substrates and associated transporters, the roles of insulin and of lipid droplets, the emerging role of metabolism in microglia, mysteries about the major brain cofactor and signaling molecule NAD+ , as well as unsolved problems underlying brain metabolism in pathologies such as traumatic brain injury, epilepsy, and metabolic downregulation during hibernation. It describes our current level of understanding of these facets of brain energy metabolism as well as a roadmap for future research.

Keywords:  GLUT4; acetate; aerobic glycolysis; insulin; noradrenaline

DOI:  https://doi.org/10.1111/jnc.16032
J Am Soc Nephrol. 2024 Jan 11.

Renal Mitochondrial ATP Transporter Ablation Ameliorates Obesity-Induced Chronic Kidney Disease.

Anna Permyakova, Sharleen Hamad, Liad Hinden, Saja Baraghithy, Aviram Kogot-Levin, Omri Yosef, Ori Shalev, Manish Kumar Tripathi, Haitham Amal, Abhishek Basu, Muhammad Arif, Resat Cinar, George Kunos, Michael Berger, Gil Leibowitz, Joseph Tam.

BACKGROUND: The impairment in ATP production and transport in renal proximal tubule cells (RPTCs) has been linked to the pathogenesis of obesity-induced chronic kidney disease (CKD). This condition is characterized by kidney dysfunction, inflammation, lipotoxicity, and fibrosis. Here we investigated the role of adenine nucleotide transporter 2 (ANT2), which serves as the primary regulator of cellular ATP content in RPTCs, in the development of obesity-induced CKD.
METHODS: We generated RPTC-specific Ant2 knockout (RPTC-Ant2-/-) mice, which were then subjected to a 24-week high-fat diet feeding regimen. We conducted comprehensive assessment of renal morphology, function, and metabolic alterations of these mice. Additionally, we employed large-scale transcriptomics, proteomics, and metabolomics analyses to gain insights into the role of ANT2 in regulating mitochondrial function, RPTC physiology, and overall renal health.
RESULTS: Our findings revealed that obese RPTC-Ant2-/- mice displayed preserved renal morphology and function, along with a notable absence of kidney lipotoxicity and fibrosis. The depletion of Ant2 in RPTCs led to a fundamental rewiring of their primary metabolic program. Specifically, these cells shifted from oxidizing fatty acids as their primary energy source to favoring aerobic glycolysis, a phenomenon mediated by the testis-selective Ant4.
CONCLUSIONS: We propose a significant role for RPTC-Ant2 in the development of obesity-induced CKD. The nullification of RPTC-Ant2 triggers a cascade of cellular mechanisms, including mitochondrial protection, enhanced RPTC survival, and ultimately the preservation of kidney function. These findings shed new light on the complex metabolic pathways contributing to CKD development and suggest potential therapeutic targets for this condition.

DOI: https://doi.org/10.1681/ASN.0000000000000294
Oncogene. 2024 Jan 06.

DMT1-dependent endosome-mitochondria interactions regulate mitochondrial iron translocation and metastatic outgrowth.

Jonathan Barra, Isaiah Crosbourne, Cassandra L Roberge, Ramon Bossardi-Ramos, Janine S A Warren, Kailie Matteson, Ling Wang, Frances Jourd'heuil, Sergey M Borisov, Erin Bresnahan, Jose Javier Bravo-Cordero, Ruslan I Dmitriev, David Jourd'heuil, Alejandro P Adam, John M Lamar, David T Corr, Margarida M Barroso.

Transient early endosome (EE)-mitochondria interactions can mediate mitochondrial iron translocation, but the associated mechanisms are still elusive. We showed that Divalent Metal Transporter 1 (DMT1) sustains mitochondrial iron translocation via EE-mitochondria interactions in triple-negative MDA-MB-231, but not in luminal A T47D breast cancer cells. DMT1 silencing increases labile iron pool (LIP) levels and activates PINK1/Parkin-dependent mitophagy in MDA-MB-231 cells. Mitochondrial bioenergetics and the iron-associated protein profile were altered by DMT1 silencing and rescued by DMT1 re-expression. Transcriptomic profiles upon DMT1 silencing are strikingly different between 2D and 3D culture conditions, suggesting that the environment context is crucial for the DMT1 knockout phenotype observed in MDA-MB-231 cells. Lastly, in vivo lung metastasis assay revealed that DMT1 silencing promoted the outgrowth of lung metastatic nodules in both human and murine models of triple-negative breast cancer cells. These findings reveal a DMT1-dependent pathway connecting EE-mitochondria interactions to mitochondrial iron translocation and metastatic fitness of breast cancer cells.

DOI: https://doi.org/10.1038/s41388-023-02933-x
Cells. 2024 Jan 04. pii: 103. [Epub ahead of print]13(1):

Neuronal Autophagy: Regulations and Implications in Health and Disease.

Caroline Liénard, Alexandre Pintart, Pascale Bomont.

  Autophagy is a major degradative pathway that plays a key role in sustaining cell homeostasis, integrity, and physiological functions. Macroautophagy, which ensures the clearance of cytoplasmic components engulfed in a double-membrane autophagosome that fuses with lysosomes, is orchestrated by a complex cascade of events. Autophagy has a particularly strong impact on the nervous system, and mutations in core components cause numerous neurological diseases. We first review the regulation of autophagy, from autophagosome biogenesis to lysosomal degradation and associated neurodevelopmental/neurodegenerative disorders. We then describe how this process is specifically regulated in the axon and in the somatodendritic compartment and how it is altered in diseases. In particular, we present the neuronal specificities of autophagy, with the spatial control of autophagosome biogenesis, the close relationship of maturation with axonal transport, and the regulation by synaptic activity. Finally, we discuss the physiological functions of autophagy in the nervous system, during development and in adulthood.

Keywords:  autophagy; compartmentalisation; neurodegeneration; neurodevelopment; regulations

DOI:  https://doi.org/10.3390/cells13010103
bioRxiv. 2023 Dec 22. pii: 2023.12.22.573059. [Epub ahead of print]

Metabolomics profiling reveals distinct, sex-specific signatures in the serum and brain metabolomes in the mouse models of Alzheimer's disease.

Ravi S Pandey, Mattias Arnold, Richa Batra, Jan Krumsiek, Kevin P Kotredes, Dylan Garceau, Harriet Williams, Michael Sasner, Gareth R Howell, Rima Kaddurah-Daouk, Gregory W Carter.

   INTRODUCTION: Increasing evidence suggests that metabolic impairments contribute to early Alzheimer's disease (AD) mechanisms and subsequent dementia. Signals in metabolic pathways conserved across species provides a promising entry point for translation. METHODS: We investigated differences of serum and brain metabolites between the early-onset 5XFAD and late-onset LOAD1 (APOE4.Trem2*R47H) mouse models of AD to C57BL/6J controls at six months of age.
RESULTS: We identified sex differences for several classes of metabolites, such as glycerophospholipids, sphingolipids, and amino acids. Metabolic signatures were notably different between brain and serum in both mouse models. The 5XFAD mice exhibited stronger differences in brain metabolites, whereas LOAD1 mice showed more pronounced differences in serum.
DISCUSSION: Several of our findings were consistent with results in humans, showing glycerophospholipids reduction in serum of APOE4 carriers and replicating the serum metabolic imprint of the APOE4 genotype. Our work thus represents a significant step towards translating metabolic dysregulation from model organisms to human AD.

Keywords:  5XFAD; APOE4; Alzheimer’s disease; Metabolomics; animal models

DOI:  https://doi.org/10.1101/2023.12.22.573059
Sci Rep. 2024 01 08. 14(1): 845

Radiation-induced changes in energy metabolism result in mitochondrial dysfunction in salivary glands.

Lauren G Buss, Brenna A Rheinheimer, Kirsten H Limesand.

Salivary glands are indirectly damaged during radiotherapy for head and neck cancer, resulting in acute and chronic hyposalivation. Current treatments for radiation-induced hyposalivation do not permanently restore function to the gland; therefore, more mechanistic understanding of the damage response is needed to identify therapeutic targets for lasting restoration. Energy metabolism reprogramming has been observed in cancer and wound healing models to provide necessary fuel for cell proliferation; however, there is limited understanding of alterations in energy metabolism reprogramming in tissues that fail to heal. We measured extracellular acidification and oxygen consumption rates, assessed mitochondrial DNA copy number, and tested fuel dependency of irradiated primary salivary acinar cells. Radiation treatment leads to increases in glycolytic flux, oxidative phosphorylation, and ATP production rate at acute and intermediate time points. In contrast, at chronic radiation time points there is a significant decrease in glycolytic flux, oxidative phosphorylation, and ATP production rate. Irradiated salivary glands exhibit significant decreases in spare respiratory capacity and increases in mitochondrial DNA copy number at days 5 and 30 post-treatment, suggesting a mitochondrial dysfunction phenotype. These results elucidate kinetic changes in energy metabolism reprogramming of irradiated salivary glands that may underscore the chronic loss of function phenotype.

DOI: https://doi.org/10.1038/s41598-023-50877-9
Trends Endocrinol Metab. 2024 Jan 10. pii: S1043-2760(23)00250-3. [Epub ahead of print]

Recreating metabolic interactions of the tumour microenvironment.

Rodrigo Curvello, Nikolaus Berndt, Sandra Hauser, Daniela Loessner.

  Tumours are heterogeneous tissues containing diverse populations of cells and an abundant extracellular matrix (ECM). This tumour microenvironment prompts cancer cells to adapt their metabolism to survive and grow. Besides epigenetic factors, the metabolism of cancer cells is shaped by crosstalk with stromal cells and extracellular components. To date, most experimental models neglect the complexity of the tumour microenvironment and its relevance in regulating the dynamics of the metabolism in cancer. We discuss emerging strategies to model cellular and extracellular aspects of cancer metabolism. We highlight cancer models based on bioengineering, animal, and mathematical approaches to recreate cell-cell and cell-matrix interactions and patient-specific metabolism. Combining these approaches will improve our understanding of cancer metabolism and support the development of metabolism-targeting therapies.

Keywords:  cancer metabolism; cancer models; mathematical models; tumour microenvironment

DOI:  https://doi.org/10.1016/j.tem.2023.12.005
J Cell Sci. 2024 Jan 01. pii: jcs260986. [Epub ahead of print]137(1):

Cristae shaping and dynamics in mitochondrial function.

Claire Caron, Giulia Bertolin.

  Mitochondria are multifunctional organelles of key importance for cell homeostasis. The outer mitochondrial membrane (OMM) envelops the organelle, and the inner mitochondrial membrane (IMM) is folded into invaginations called cristae. As cristae composition and functions depend on the cell type and stress conditions, they recently started to be considered as a dynamic compartment. A number of proteins are known to play a role in cristae architecture, such as OPA1, MIC60, LETM1, the prohibitin (PHB) complex and the F1FO ATP synthase. Furthermore, phospholipids are involved in the maintenance of cristae ultrastructure and dynamics. The use of new technologies, including super-resolution microscopy to visualize cristae dynamics with superior spatiotemporal resolution, as well as high-content techniques and datasets have not only allowed the identification of new cristae proteins but also helped to explore cristae plasticity. However, a number of open questions remain in the field, such as whether cristae-resident proteins are capable of changing localization within mitochondria, or whether mitochondrial proteins can exit mitochondria through export. In this Review, we present the current view on cristae morphology, stability and composition, and address important outstanding issues that might pave the way to future discoveries.

Keywords:  Cristae; Cristae dynamics; High-content approaches; Mitochondria; Quantitative microscopy

DOI:  https://doi.org/10.1242/jcs.260986
Front Aging Neurosci. 2023 ;15 1326127

O-GlcNAc regulates the mitochondrial integrated stress response by regulating ATF4.

Ibtihal M Alghusen, Marisa S Carman, Heather Wilkins, Sophiya John Ephrame, Amy Qiang, Wagner B Dias, Halyna Fedosyuk, Aspin R Denson, Russell H Swerdlow, Chad Slawson.

   Background: Accumulation of mitochondrial dysfunctional is a hallmark of age-related neurodegeneration including Alzheimer's disease (AD). Impairment of mitochondrial quality control mechanisms leading to the accumulation of damaged mitochondria and increasing neuronal stress. Therefore, investigating the basic mechanisms of how mitochondrial homeostasis is regulated is essential. Herein, we investigate the role of O-GlcNAcylation, a single sugar post-translational modification, in controlling mitochondrial stress-induced transcription factor Activating Transcription Factor 4 (ATF4). Mitochondrial dysfunction triggers the integrated stress response (ISRmt), in which the phosphorylation of eukaryotic translation initiation factor 2α results in the translation of ATF4.
Methods: We used patient-derived induced pluripotent stem cells, a transgenic mouse model of AD, SH-SY5Y neuroblastoma and HeLa cell-lines to examine the effect of sustained O-GlcNAcase inhibition by Thiamet-G (TMG) on ISRmt using biochemical analyses.
Results: We show that TMG elevates ATF4 protein levels upon mitochondrial stress in SH-SY5Y neuroblastoma and HeLa cell-lines. An indirect downstream target of ATF4 mitochondrial chaperone glucose-regulated protein 75 (GRP75) is significantly elevated. Interestingly, knock-down of O-GlcNAc transferase (OGT), the enzyme that adds O-GlcNAc, in SH-SY5Y increases ATF4 protein and mRNA expression. Additionally, ATF4 target gene Activating Transcription Factor 5 (ATF5) is significantly elevated at both the protein and mRNA level. Brains isolated from TMG treated mice show elevated levels of ATF4 and GRP75. Importantly, ATF4 occupancy increases at the ATF5 promoter site in brains isolated from TMG treated mice suggesting that O-GlcNAc is regulating ATF4 targeted gene expression. Interestingly, ATF4 and GRP75 are not induced in TMG treated familial Alzheimer's Disease mice model. The same results are seen in a human in vitro model of AD.
Conclusion: Together, these results indicate that in healthy conditions, O-GlcNAc regulates the ISRmt through regulating ATF4, while manipulating O-GlcNAc in AD has no effect on ISRmt.

Keywords:  Alzheimer’s disease; O-GlcNAc; activating transcription factor 4 (ATF4); integrated stress response; mitochondrial stress

DOI:  https://doi.org/10.3389/fnagi.2023.1326127
EMBO J. 2024 Jan 11.

Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis.

Ching-Fang Chang, Amanda L Gunawan, Irene Liparulo, Peter-James H Zushin, Kaitlyn Vitangcol, Greg A Timblin, Kaoru Saijo, Biao Wang, Güneş Parlakgül, Ana Paula Arruda, Andreas Stahl.

  Coenzyme Q (CoQ) is essential for mitochondrial respiration and required for thermogenic activity in brown adipose tissues (BAT). CoQ deficiency leads to a wide range of pathological manifestations, but mechanistic consequences of CoQ deficiency in specific tissues, such as BAT, remain poorly understood. Here, we show that pharmacological or genetic CoQ deficiency in BAT leads to stress signals causing accumulation of cytosolic mitochondrial RNAs and activation of the eIF2α kinase PKR, resulting in activation of the integrated stress response (ISR) with suppression of UCP1 but induction of FGF21 expression. Strikingly, despite diminished UCP1 levels, BAT CoQ deficiency displays increased whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high-fat diets (HFD). In line with enhanced metabolic rates, BAT and inguinal white adipose tissue (iWAT) interorgan crosstalk caused increased browning of iWAT in BAT-specific CoQ deficient animals. This mitohormesis-like effect depends on the ATF4-FGF21 axis and BAT-secreted FGF21, revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies.

Keywords:  Brown Adipose Tissue; Coenzyme Q; FGF21; Mitochondrial Unfolded Protein Response; Mitohormesis

DOI:  https://doi.org/10.1038/s44318-023-00008-x
bioRxiv. 2023 Dec 24. pii: 2023.12.24.573250. [Epub ahead of print]

Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability.

Keene L Abbott, Ahmed Ali, Bradley I Reinfeld, Amy Deik, Sonu Subudhi, Madelyn D Landis, Rachel A Hongo, Kirsten L Young, Tenzin Kunchok, Christopher S Nabel, Kayla D Crowder, Johnathan R Kent, Maria Lucia L Madariaga, Rakesh K Jain, Kathryn E Beckermann, Caroline A Lewis, Clary B Clish, Alexander Muir, W Kimryn Rathmell, Jeffrey C Rathmell, Matthew G Vander Heiden.

The tumor microenvironment is a determinant of cancer progression and therapeutic efficacy, with nutrient availability playing an important role. Although it is established that the local abundance of specific nutrients defines the metabolic parameters for tumor growth, the factors guiding nutrient availability in tumor compared to normal tissue and blood remain poorly understood. To define these factors in renal cell carcinoma (RCC), we performed quantitative metabolomic and comprehensive lipidomic analyses of tumor interstitial fluid (TIF), adjacent normal kidney interstitial fluid (KIF), and plasma samples collected from patients. TIF nutrient composition closely resembles KIF, suggesting that tissue-specific factors unrelated to the presence of cancer exert a stronger influence on nutrient levels than tumor-driven alterations. Notably, select metabolite changes consistent with known features of RCC metabolism are found in RCC TIF, while glucose levels in TIF are not depleted to levels that are lower than those found in KIF. These findings inform tissue nutrient dynamics in RCC, highlighting a dominant role of non-cancer driven tissue factors in shaping nutrient availability in these tumors.

DOI: https://doi.org/10.1101/2023.12.24.573250