bims-camemi 2021-12-26 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2021–12–26
forty-four papers selected by
Christian Frezza, , University of Cambridge, MRC Cancer Unit

Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism.
Signalling metabolite L-2-hydroxyglutarate activates the transcription factor HIF-1α in lipopolysaccharide-activated macrophages.
Hyaluronic acid fuels pancreatic cancer cell growth.
Multi-Omic Metabolic Enrichment Network Analysis reveals metabolite-protein physical interaction subnetworks altered in cancer.
Post-translational modifications on mitochondrial metabolic enzymes in cancer.
Reuterin in the healthy gut microbiome suppresses colorectal cancer growth through altering redox balance.
Targeting Mitochondrial OXPHOS and Their Regulatory Signals in Prostate Cancers.
Inhibition of the Anti-Apoptotic Bcl-2 Family by BH3 Mimetics Sensitize the Mitochondrial Permeability Transition Pore Through Bax and Bak.
Coordinated reprogramming of metabolism and cell function in adipocytes from proliferation to differentiation.
Diethyl Succinate Modulates Microglial Polarization and Activation by Reducing Mitochondrial Fission and Cellular ROS.
ATAD3A has a scaffolding role regulating mitochondria inner membrane structure and protein assembly.
Microbial metabolite delta-valerobetaine is a diet-dependent obesogen.
Valine tRNA levels and availability regulate complex I assembly in leukaemia.
Nrf2 for protection against oxidant generation and mitochondrial damage in cardiac injury.
A microbial metabolite linked to fat accumulation.
Acetyl-CoA production by specific metabolites promotes cardiac repair after myocardial infarction via histone acetylation.
Mitochondrial DNA damage as driver of cellular outcomes.
Mitophagy in Yeast: Molecular Mechanism and Regulation.
Dinner is served, sir: Fighting cancer with the right diet.
A counter-enzyme complex regulates glutamate metabolism in Bacillus subtilis.
Understanding circadian regulation of mammalian cell function, protein homeostasis, and metabolism.
Protein Quality Control at the Mitochondrial Surface.
AMPK-Mediated Metabolic Switching Is High Effective for Phytochemical Levo-Tetrahydropalmatine (l-THP) to Reduce Hepatocellular Carcinoma Tumor Growth.
Mitochondrial Redox Regulations and Redox Biology of Mitochondria.
On the Design Principles of Metabolic Flux Sensing.
Interdependent Regulation of Polycystin Expression Influences Starvation-Induced Autophagy and Cell Death.
Mitochondrial glutamine metabolism regulates sensitivity of cancer cells after chemotherapy via amphiregulin.
Extracellular citrate and metabolic adaptations of cancer cells.
Cancer metabolism and dietary interventions.
Clone competition as a mechanism to reduce tumor formation.
Tissue metabolites in diffuse glioma and their modulations by IDH1 mutation, histology and treatment.
Management of SHDB positive patient with metastatic bilateral giant retroperitoneal paragangliomas.
Breast Cancer Cell Subtypes Display Different Metabolic Phenotypes That Correlate with Their Clinical Classification.
Metabolic reprogramming during hyperammonemia targets mitochondrial function and postmitotic senescence.
Astroglial ER-mitochondria calcium transfer mediates endocannabinoid-dependent synaptic integration.
Mitochondrial complex I inhibitors suppress tumor growth through concomitant acidification of the intra- and extracellular environment.
Lipid droplet availability affects neural stem/progenitor cell metabolism and proliferation.
Using virtual interviewing to create a more accessible hybrid academic job market.
BCL-2-family protein tBID can act as a BAX-like effector of apoptosis.
Complexity against current cancer research - are we on the wrong track?
Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer.
Ionic Regulation of T-Cell Function and Anti-Tumour Immunity.
The cholesterol pathway: impact on immunity and cancer.
Glycolysis under Circadian Control.

Elife. 2021 Dec 23. pii: e72593. [Epub ahead of print]10

Disruption of the TCA cycle reveals an ATF4-dependent integration of redox and amino acid metabolism.

Dylan Gerard Ryan, Ming Yang, Hiran A Prag, Giovanny Rodriguez Blanco, Efterpi Nikitopoulou, Marc Segarra-Mondejar, Christopher A Powell, Tim Young, Nils Burger, Jan Lj Miljkovic, Michal Minczuk, Michael P Murphy, Alex von Kriegsheim, Christian Frezza.

  The Tricarboxylic Acid Cycle (TCA) cycle is arguably the most critical metabolic cycle in physiology and exists as an essential interface coordinating cellular metabolism, bioenergetics, and redox homeostasis. Despite decades of research, a comprehensive investigation into the consequences of TCA cycle dysfunction remains elusive. Here, we targeted two TCA cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDH), and combined metabolomics, transcriptomics, and proteomics analyses to fully appraise the consequences of TCA cycle inhibition (TCAi) in murine kidney epithelial cells. Our comparative approach shows that TCAi elicits a convergent rewiring of redox and amino acid metabolism dependent on the activation of ATF4 and the integrated stress response (ISR). Furthermore, we also uncover a divergent metabolic response, whereby acute FHi, but not SDHi, can maintain asparagine levels via reductive carboxylation and maintenance of cytosolic aspartate synthesis. Our work highlights an important interplay between the TCA cycle, redox biology and amino acid homeostasis.

Keywords:  biochemistry; cell biology; chemical biology; mouse

DOI:  https://doi.org/10.7554/eLife.72593
J Biol Chem. 2021 Dec 17. pii: S0021-9258(21)01311-9. [Epub ahead of print] 101501

Signalling metabolite L-2-hydroxyglutarate activates the transcription factor HIF-1α in lipopolysaccharide-activated macrophages.

Niamh C Williams, Dylan G Ryan, Ana S H Costa, Evanna L Mills, Mark P Jedrychowski, Suzanne M Cloonan, Christian Frezza, Luke A O'Neill.

  Activated macrophages undergo metabolic reprogramming which not only supports their energetic demands but also allows for the production of specific metabolites that function as signalling molecules. Several Krebs cycle, or Krebs cycle-derived metabolites, including succinate, α-ketoglutarate and itaconate, have recently been shown to modulate macrophage function. The accumulation of 2-hydroxyglutarate (2HG) has also been well documented in transformed cells, and more recently shown to play a role in T cell and dendritic cell function. Here we have found that the abundance of both enantiomers of 2HG are increased in LPS-activated macrophages. We show that L-2HG, but not D-2HG, can promote the expression of the proinflammatory cytokine IL-1β and the adoption of an inflammatory, highly glycolytic metabolic state. These changes are likely mediated through activation of the transcription factor hypoxia inducible factor-1α (HIF-1α) by L-2HG, a known inhibitor of the HIF prolyl hydroxylases. Expression of the enzyme responsible for L-2HG degradation, L-2HG dehydrogenase (L-2HGDH), was also found to be decreased in LPS-stimulated macrophages and may therefore also contribute to L-2HG accumulation. Finally, over-expression of L-2HGDH in HEK293 TLR4/MD2/CD14 cells inhibited HIF-1α activation by LPS, whilst knockdown of L-2HGDH in macrophages boosted the induction of HIF-1α-dependent genes, as well as increasing LPS-induced HIF-1α activity. Taken together, this study therefore identifies L-2HG as a metabolite that can regulate HIF-1α in macrophages.

Keywords:  L-2-hydroxyglutarate; glycolysis; hypoxia‐inducible factor (HIF); immunometabolism; inflammation; interleukin 1β (IL‐1β); macrophage

DOI:  https://doi.org/10.1016/j.jbc.2021.101501
Elife. 2021 Dec 24. pii: e62645. [Epub ahead of print]10

Hyaluronic acid fuels pancreatic cancer cell growth.

Peter K Kim, Christopher J Halbrook, Samuel A Kerk, Megan Radyk, Stephanie Wisner, Daniel M Kremer, Peter Sajjakulnukit, Anthony Andren, Sean W Hou, Ayush Trivedi, Galloway Thurston, Abhinav Anand, Liang Yan, Lucia Salamanca-Cardona, Samuel D Welling, Li Zhang, Matthew R Pratt, Kayvan R Keshari, Haoqiang Ying, Costas Lyssiotis.

  Rewired metabolism is a hallmark of pancreatic ductal adenocarcinomas (PDA). Previously, we demonstrated that PDA cells enhance glycosylation precursor biogenesis through the hexosamine biosynthetic pathway (HBP) via activation of the rate limiting enzyme, glutamine-fructose 6-phosphate amidotransferase 1 (GFAT1). Here, we genetically ablated GFAT1 in human PDA cell lines, which completely blocked proliferation in vitro and led to cell death. In contrast, GFAT1 knockout did not preclude the growth of human tumor xenografts in mice, suggesting that cancer cells can maintain fidelity of glycosylation precursor pools by scavenging nutrients from the tumor microenvironment. We found that hyaluronic acid (HA), an abundant carbohydrate polymer in pancreatic tumors composed of repeating N-acetyl-glucosamine (GlcNAc) and glucuronic acid sugars, can bypass GFAT1 to refuel the HBP via the GlcNAc salvage pathway. Together, these data show HA can serve as a nutrient fueling PDA metabolism beyond its previously appreciated structural and signaling roles.

Keywords:  cancer biology; human; mouse

DOI:  https://doi.org/10.7554/eLife.62645
Mol Cell Proteomics. 2021 Dec 18. pii: S1535-9476(21)00161-4. [Epub ahead of print] 100189

Multi-Omic Metabolic Enrichment Network Analysis reveals metabolite-protein physical interaction subnetworks altered in cancer.

Benjamin C Blum, Weiwei Lin, Matthew L Lawton, Qian Liu, Julian Kwan, Isabella Turcinovic, Ryan Hekman, Pingzhao Hu, Andrew Emili.

  Metabolism is recognized as an important driver of cancer progression and other complex diseases, but global metabolite profiling remains a challenge. Protein expression profiling is often a poor proxy since existing pathway enrichment models provide an incomplete mapping between the proteome and metabolism. To overcome these gaps, we introduce MOMENTA, an integrative multi-omic data analysis framework for more accurately deducing metabolic pathway changes from proteomics data alone in a gene set analysis context by leveraging protein interaction networks to extend annotated metabolic models. We apply MOMENTA to proteomic data from diverse cancer cell lines and human tumors to demonstrate its utility at revealing variation in metabolic pathway activity across cancer types, which we verify using independent metabolomics measurements. The novel metabolic networks we uncover in breast cancer and other tumors are linked to clinical outcomes, underscoring the pathophysiological relevance of the findings.

Keywords:  Cancer; Multi-omic; Networks; Proteomics; Systems Biology

DOI:  https://doi.org/10.1016/j.mcpro.2021.100189
Free Radic Biol Med. 2021 Dec 17. pii: S0891-5849(21)01116-3. [Epub ahead of print]179 11-23

Post-translational modifications on mitochondrial metabolic enzymes in cancer.

Yunhua Peng, Huadong Liu, Jiankang Liu, Jiangang Long.

  Mitochondrion is the powerhouse of the cell. The research of nearly a century has expanded our understanding of mitochondrion, far beyond the view that mitochondrion is an important energy generator of cells. During the initiation, growth and survival of tumor cells, significant mitochondrial metabolic changes have taken place in the important enzymes of respiratory chain and tricarboxylic acid cycle, mitochondrial biogenesis and dynamics, oxidative stress regulation and molecular signaling. Therefore, mitochondrial metabolic proteins are the key mediators of tumorigenesis. Post-translational modification is the molecular switch that regulates protein function. Understanding how these mitochondria-related post-translational modification function during tumorigenesis will bring new ideas for the next generation of cancer treatment.

Keywords:  Metabolism; Mitochondrial biogenesis; Mitophagy; OXPHOS; Post-translational modification; TCA cycle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.12.264
Cancer Cell. 2021 Dec 14. pii: S1535-6108(21)00613-9. [Epub ahead of print]

Reuterin in the healthy gut microbiome suppresses colorectal cancer growth through altering redox balance.

Hannah N Bell, Ryan J Rebernick, Joshua Goyert, Rashi Singhal, Miljan Kuljanin, Samuel A Kerk, Wesley Huang, Nupur K Das, Anthony Andren, Sumeet Solanki, Shannon L Miller, Peter K Todd, Eric R Fearon, Costas A Lyssiotis, Steven P Gygi, Joseph D Mancias, Yatrik M Shah.

  Microbial dysbiosis is a colorectal cancer (CRC) hallmark and contributes to inflammation, tumor growth, and therapy response. Gut microbes signal via metabolites, but how the metabolites impact CRC is largely unknown. We interrogated fecal metabolites associated with mouse models of colon tumorigenesis with varying mutational load. We find that microbial metabolites from healthy mice or humans are growth-repressive, and this response is attenuated in mice and patients with CRC. Microbial profiling reveals that Lactobacillus reuteri and its metabolite, reuterin, are downregulated in mouse and human CRC. Reuterin alters redox balance, and reduces proliferation and survival in colon cancer cells. Reuterin induces selective protein oxidation and inhibits ribosomal biogenesis and protein translation. Exogenous Lactobacillus reuteri restricts colon tumor growth, increases tumor reactive oxygen species, and decreases protein translation in vivo. Our findings indicate that a healthy microbiome and specifically, Lactobacillus reuteri, is protective against CRC through microbial metabolite exchange.

Keywords:  Lactobacillus reuteri; Microbiome; Reuterin; colorectal cancer; metabolites; protein oxidation

DOI:  https://doi.org/10.1016/j.ccell.2021.12.001
Int J Mol Sci. 2021 Dec 14. pii: 13435. [Epub ahead of print]22(24):

Targeting Mitochondrial OXPHOS and Their Regulatory Signals in Prostate Cancers.

Chia-Lin Chen, Ching-Yu Lin, Hsing-Jien Kung.

  Increasing evidence suggests that tumor development requires not only oncogene/tumor suppressor mutations to drive the growth, survival, and metastasis but also metabolic adaptations to meet the increasing energy demand for rapid cellular expansion and to cope with the often nutritional and oxygen-deprived microenvironment. One well-recognized strategy is to shift the metabolic flow from oxidative phosphorylation (OXPHOS) or respiration in mitochondria to glycolysis or fermentation in cytosol, known as Warburg effects. However, not all cancer cells follow this paradigm. In the development of prostate cancer, OXPHOS actually increases as compared to normal prostate tissue. This is because normal prostate epithelial cells divert citrate in mitochondria for the TCA cycle to the cytosol for secretion into seminal fluid. The sustained level of OXPHOS in primary tumors persists in progression to an advanced stage. As such, targeting OXPHOS and mitochondrial activities in general present therapeutic opportunities. In this review, we summarize the recent findings of the key regulators of the OXPHOS pathway in prostate cancer, ranging from transcriptional regulation, metabolic regulation to genetic regulation. Moreover, we provided a comprehensive update of the current status of OXPHOS inhibitors for prostate cancer therapy. A challenge of developing OXPHOS inhibitors is to selectively target cancer mitochondria and spare normal counterparts, which is also discussed.

Keywords:  OXPHOS; cancer therapy; mitochondria

DOI:  https://doi.org/10.3390/ijms222413435
Front Cell Dev Biol. 2021 ;9 765973

Inhibition of the Anti-Apoptotic Bcl-2 Family by BH3 Mimetics Sensitize the Mitochondrial Permeability Transition Pore Through Bax and Bak.

Pooja Patel, Arielys Mendoza, Dexter J Robichaux, Meng C Wang, Xander H T Wehrens, Jason Karch.

  Mitochondrial permeability transition pore (MPTP)-dependent necrosis contributes to numerous pathologies in the heart, brain, and skeletal muscle. The MPTP is a non-selective pore in the inner mitochondrial membrane that is triggered by high levels of matrix Ca2+, and sustained opening leads to mitochondrial dysfunction. Although the MPTP is defined by an increase in inner mitochondrial membrane permeability, the expression of pro-apoptotic Bcl-2 family members, Bax and Bak localization to the outer mitochondrial membrane is required for MPTP-dependent mitochondrial dysfunction and subsequent necrotic cell death. Contrary to the role of Bax and Bak in apoptosis, which is dependent on their oligomerization, MPTP-dependent necrosis does not require oligomerization as monomeric/inactive forms of Bax and Bak can facilitate mitochondrial dysfunction. However, the relationship between Bax and Bak activation/oligomerization and MPTP sensitization remains to be explored. Here, we use a combination of in vitro and ex vivo approaches to determine the role of the anti-apoptotic Bcl-2 family members, which regulate Bax/Bak activity, in necrotic cell death and MPTP sensitivity. To study the role of each predominantly expressed anti-apoptotic Bcl-2 family member (i.e., Mcl-1, Bcl-2, and Bcl-xL) in MPTP regulation, we utilize various BH3 mimetics that specifically bind to and inhibit each. We determined that the inhibition of each anti-apoptotic Bcl-2 family member lowers mitochondrial calcium retention capacity and sensitizes MPTP opening. Furthermore, the inhibition of each Bcl-2 family member exacerbates both apoptotic and necrotic cell death in vitro in a Bax/Bak-dependent manner. Our findings suggests that mitochondrial Ca2+ retention capacity and MPTP sensitivity is influenced by Bax/Bak activation/oligomerization on the outer mitochondrial membrane, providing further evidence of the crosstalk between the apoptotic and necrotic cell death pathways.

Keywords:  BCL-2 family; BH3 mimetics; calcium; mitochondria; mitochondrial dysfunction; necrosis; permeability transition

DOI:  https://doi.org/10.3389/fcell.2021.765973
Metab Eng. 2021 Dec 17. pii: S1096-7176(21)00191-9. [Epub ahead of print]69 221-230

Coordinated reprogramming of metabolism and cell function in adipocytes from proliferation to differentiation.

Eleanor H Oates, Maciek R Antoniewicz.

  Adipose tissue plays a major role in regulating lipid and energy homeostasis by storing excess nutrients, releasing energetic substrates through lipolysis, and regulating metabolism of other tissues and organs through endocrine and paracrine signaling. Adipocytes within fat tissues store excess nutrients through increased cell number (hyperplasia), increased cell size (hypertrophy), or both. The differentiation of pre-adipocytes into mature lipid-accumulating adipocytes requires a complex interaction of metabolic pathways that is still incompletely understood. Here, we applied parallel labeling experiments and 13C-metabolic flux analysis to quantify precise metabolic fluxes in proliferating and differentiated 3T3-L1 cells, a widely used model to study adipogenesis. We found that morphological and biomass composition changes in adipocytes were accompanied by significant shifts in metabolic fluxes, encompassing all major metabolic pathways. In contrast to proliferating cells, differentiated adipocytes 1) increased glucose uptake and redirected glucose utilization from lactate production to lipogenesis and energy generation; 2) increased pathway fluxes through glycolysis, oxidative pentose phosphate pathway and citric acid cycle; 3) reduced lactate secretion, resulting in increased ATP generation via oxidative phosphorylation; 4) rewired glutamine metabolism, from glutaminolysis to de novo glutamine synthesis; 5) increased cytosolic NADPH production, driven mostly by increased cytosolic malic enzyme flux; 6) increased production of monounsaturated C16:1; and 7) activated a mitochondrial pyruvate cycle through simultaneous activity of pyruvate carboxylase, malate dehydrogenase and malic enzyme. Taken together, these results quantitatively highlight the complex interplay between pathway fluxes and cell function in adipocytes, and suggest a functional role for metabolic reprogramming in adipose differentiation and lipogenesis.

Keywords:  3T3-L1 cells; Adipocytes; Adipogensis; Differentiation; Metabolism; de novo lipogenesis

DOI:  https://doi.org/10.1016/j.ymben.2021.12.005
Metabolites. 2021 Dec 08. pii: 854. [Epub ahead of print]11(12):

Diethyl Succinate Modulates Microglial Polarization and Activation by Reducing Mitochondrial Fission and Cellular ROS.

Lixiang Wang, Yanli Zhang, Magdalena Kiprowska, Yuqi Guo, Ken Yamamoto, Xin Li.

  Succinate is a metabolite in the tricarboxylic acid cycle (TCA) which plays a central role in mitochondrial activity. Excess succinate is known to be transported out of the cytosol, where it activates a succinate receptor (SUCNR1) to enhance inflammation through macrophages in various contexts. In addition, the intracellular role of succinate beyond an intermediate metabolite and prior to its extracellular release is also important to the polarization of macrophages. However, the role of succinate in microglial cells has not been characterized. Lipopolysaccharide (LPS) stimulates the elevation of intracellular succinate levels. To reveal the function of intracellular succinate associated with LPS-stimulated inflammatory response in microglial cells, we assessed the levels of ROS, cytokine production and mitochondrial fission in the primary microglia pretreated with cell-permeable diethyl succinate mimicking increased intracellular succinate. Our results suggest that elevated intracellular succinate exerts a protective role in the primary microglia by preventing their conversion into the pro-inflammatory M1 phenotype induced by LPS. This protective effect is SUCNR1-independent and mediated by reduced mitochondrial fission and cellular ROS production.

Keywords:  LPS; dynamin-related protein; microglia; mitochondrial fission; succinate

DOI:  https://doi.org/10.3390/metabo11120854
Cell Rep. 2021 Dec 21. pii: S2211-1247(21)01635-1. [Epub ahead of print]37(12): 110139

ATAD3A has a scaffolding role regulating mitochondria inner membrane structure and protein assembly.

Tania Arguello, Susana Peralta, Hana Antonicka, Gabriel Gaidosh, Francisca Diaz, Ya-Ting Tu, Sofia Garcia, Ramin Shiekhattar, Antonio Barrientos, Carlos T Moraes.

  The ATPase Family AAA Domain Containing 3A (ATAD3A), is a mitochondrial inner membrane protein conserved in metazoans. ATAD3A has been associated with several mitochondrial functions, including nucleoid organization, cholesterol metabolism, and mitochondrial translation. To address its primary role, we generated a neuronal-specific conditional knockout (Atad3 nKO) mouse model, which developed a severe encephalopathy by 5 months of age. Pre-symptomatic mice showed aberrant mitochondrial cristae morphogenesis in the cortex as early as 2 months. Using a multi-omics approach in the CNS of 2-to-3-month-old mice, we found early alterations in the organelle membrane structure. We also show that human ATAD3A associates with different components of the inner membrane, including OXPHOS complex I, Letm1, and prohibitin complexes. Stochastic Optical Reconstruction Microscopy (STORM) shows that ATAD3A is regularly distributed along the inner mitochondrial membrane, suggesting a critical structural role in inner mitochondrial membrane and its organization, most likely in an ATPase-dependent manner.

Keywords:  ATAD3; cardiolipin; cristae; inner membrane; mitochondria

DOI:  https://doi.org/10.1016/j.celrep.2021.110139
Nat Metab. 2021 Dec;3(12): 1694-1705

Microbial metabolite delta-valerobetaine is a diet-dependent obesogen.

Ken H Liu, Joshua A Owens, Bejan Saeedi, Catherine E Cohen, Moriah P Bellissimo, Crystal Naudin, Trevor Darby, Samuel Druzak, Kristal Maner-Smith, Michael Orr, Xin Hu, Jolyn Fernandes, Mary Catherine Camacho, Sarah Hunter-Chang, David VanInsberghe, Chunyu Ma, Thota Ganesh, Samantha M Yeligar, Karan Uppal, Young-Mi Go, Jessica A Alvarez, Miriam B Vos, Thomas R Ziegler, Michael H Woodworth, Colleen S Kraft, Rheinallt M Jones, Eric Ortlund, Andrew S Neish, Dean P Jones.

Obesity and obesity-related metabolic disorders are linked to the intestinal microbiome. However, the causality of changes in the microbiome-host interaction affecting energy metabolism remains controversial. Here, we show the microbiome-derived metabolite δ-valerobetaine (VB) is a diet-dependent obesogen that is increased with phenotypic obesity and is correlated with visceral adipose tissue mass in humans. VB is absent in germ-free mice and their mitochondria but present in ex-germ-free conventionalized mice and their mitochondria. Mechanistic studies in vivo and in vitro show VB is produced by diverse bacterial species and inhibits mitochondrial fatty acid oxidation through decreasing cellular carnitine and mitochondrial long-chain acyl-coenzyme As. VB administration to germ-free and conventional mice increases visceral fat mass and exacerbates hepatic steatosis with a western diet but not control diet. Thus, VB provides a molecular target to understand and potentially manage microbiome-host symbiosis or dysbiosis in diet-dependent obesity.

DOI: https://doi.org/10.1038/s42255-021-00502-8
Nature. 2021 Dec 22.

Valine tRNA levels and availability regulate complex I assembly in leukaemia.

Palaniraja Thandapani, Andreas Kloetgen, Matthew T Witkowski, Christina Glytsou, Anna K Lee, Eric Wang, Jingjing Wang, Sarah E LeBoeuf, Kleopatra Avrampou, Thales Papagiannakopoulos, Aristotelis Tsirigos, Iannis Aifantis.

Although deregulation of transfer RNA (tRNA) biogenesis promotes the translation of pro-tumorigenic mRNAs in cancers1,2, the mechanisms and consequences of tRNA deregulation in tumorigenesis are poorly understood. Here we use a CRISPR-Cas9 screen to focus on genes that have been implicated in tRNA biogenesis, and identify a mechanism by which altered valine tRNA biogenesis enhances mitochondrial bioenergetics in T cell acute lymphoblastic leukaemia (T-ALL). Expression of valine aminoacyl tRNA synthetase is transcriptionally upregulated by NOTCH1, a key oncogene in T-ALL, underlining a role for oncogenic transcriptional programs in coordinating tRNA supply and demand. Limiting valine bioavailability through restriction of dietary valine intake disrupted this balance in mice, resulting in decreased leukaemic burden and increased survival in vivo. Mechanistically, valine restriction reduced translation rates of mRNAs that encode subunits of mitochondrial complex I, leading to defective assembly of complex I and impaired oxidative phosphorylation. Finally, a genome-wide CRISPR-Cas9 loss-of-function screen in differential valine conditions identified several genes, including SLC7A5 and BCL2, whose genetic ablation or pharmacological inhibition synergized with valine restriction to reduce T-ALL growth. Our findings identify tRNA deregulation as a critical adaptation in the pathogenesis of T-ALL and provide a molecular basis for the use of dietary approaches to target tRNA biogenesis in blood malignancies.

DOI: https://doi.org/10.1038/s41586-021-04244-1
Free Radic Biol Med. 2021 Dec 15. pii: S0891-5849(21)00852-2. [Epub ahead of print]

Nrf2 for protection against oxidant generation and mitochondrial damage in cardiac injury.

Qin M Chen.

Myocardial infarction is the most common form of acute coronary syndrome. Blockage of a coronary artery due to blood clotting leads to ischemia and subsequent cell death in the form of necrosis, apoptosis, necroptosis and ferroptosis. Revascularization by coronary artery bypass graft surgery or non-surgical percutaneous coronary intervention combined with pharmacotherapy is effective in relieving symptoms and decreasing mortality. However, reactive oxygen species (ROS) are generated from damaged mitochondria, NADPH oxidases, xanthine oxidase, and inflammation. Impairment of mitochondria is shown as decreased metabolic activity, increased ROS production, membrane permeability transition, and release of mitochondrial proteins into the cytoplasm. Oxidative stress activates Nrf2 transcription factor, which in turn mediates the expression of mitofusin 2 (Mfn 2) and proteasomal genes. Increased expression of Mfn2 and inhibition of mitochondrial fission due to decreased Drp1 protein by proteasomal degradation contribute to mitochondrial hyperfusion. Damaged mitochondria can be removed by mitophagy via Parkin or p62 mediated ubiquitination. Mitochondrial biogenesis compensates for the loss of mitochondria, but requires mitochondrial DNA replication and initiation of transcription or translation of mitochondrial genes. Experimental evidence supports a role of Nrf2 in mitophagy, via up-regulation of PINK1 or p62 gene expression; and in mitochondrial biogenesis, by influencing the expression of PGC-1α, NResF1, NResF2, TFAM and mitochondrial genes. Oxidative stress causes Nrf2 activation via Keap1 dissociation, de novo protein translation, and nuclear translocation related to inactivation of GSK3β. The mechanism of Keap 1 mediated Nrf2 activation has been hijacked for Nrf2 activation by small molecules derived from natural products, some of which have been shown capable of mitochondrial protection. Multiple lines of evidence support the importance of Nrf2 in protecting mitochondria and preserving or renewing energy metabolism following tissue injury.

DOI: https://doi.org/10.1016/j.freeradbiomed.2021.12.001
Nat Metab. 2021 Dec;3(12): 1594-1595

A microbial metabolite linked to fat accumulation.

Jane F Ferguson.

DOI: https://doi.org/10.1038/s42255-021-00495-4
Elife. 2021 Dec 23. pii: e60311. [Epub ahead of print]10

Acetyl-CoA production by specific metabolites promotes cardiac repair after myocardial infarction via histone acetylation.

Ienglam Lei, Shuo Tian, Wenbin Gao, Liu Liu, Yijing Guo, Paul Tang, Eugene Chen, Zhong Wang.

  Myocardial infarction (MI) is accompanied by severe energy deprivation and extensive epigenetic changes. However, how energy metabolism and chromatin modifications are interlinked during MI and heart repair has been poorly explored. Here, we examined the effect of different carbon sources that are involved in the major metabolic pathways of acetyl-CoA synthesis on myocardial infarction and found that elevation of acetyl-CoA by sodium octanoate (8C) significantly improved heart function in ischemia reperfusion (I/R) rats. Mechanistically, 8C reduced I/R injury by promoting histone acetylation which in turn activated the expression of antioxidant genes and inhibited cardiomyocyte (CM) apoptosis. Furthermore, we elucidated that 8C-promoted histone acetylation and heart repair were carried out by metabolic enzyme medium-chain acyl-CoA dehydrogenase (MCAD) and histone acetyltransferase Kat2a, suggesting that 8C dramatically improves cardiac function mainly through metabolic acetyl-CoA-mediated histone acetylation. Therefore, our study uncovers an interlinked metabolic/epigenetic network comprising 8C, acetyl-CoA, MCAD, and Kat2a to combat heart injury.

Keywords:  cell biology; mouse

DOI:  https://doi.org/10.7554/eLife.60311
Am J Physiol Cell Physiol. 2021 Dec 22.

Mitochondrial DNA damage as driver of cellular outcomes.

Cristina A Nadalutti, Sylvette Ayala-Peña, Janine H Santos.

  Mitochondria are primarily involved in energy production through the process of oxidative phosphorylation (OXPHOS). Increasing evidence has shown that mitochondrial function impacts a plethora of different cellular activities, including metabolism, epigenetics and innate immunity. Like the nucleus, mitochondria own their genetic material, which is maternally inherited. The mitochondrial DNA (mtDNA) encodes 37 genes that are solely involved in OXPHOS. Maintenance of mtDNA, through replication and repair, requires the import of nuclear DNA encoded proteins. Thus, mitochondria completely rely on the nucleus to prevent mitochondrial genetic alterations. As every cell contains hundreds to thousands of mitochondria, it follows that the shear number of organelles allow for the buffering of dysfunction - at least to some extent - before tissue homeostasis becomes impaired. Only red blood cells lack mitochondria entirely. Impaired mitochondrial function is a hallmark of aging and is involved in a number of different disorders, including neurodegenerative diseases, diabetes, cancer, and autoimmunity. While alterations in mitochondrial processes unrelated to OXPHOS, such as fusion and fission, contribute to aging and disease, maintenance of mtDNA integrity is critical for proper organellar function. Here, we focus on how mtDNA damage contributes to cellular dysfunction and health outcomes.

Keywords:  DNA repair; cellular outcomes; mitochondrial dysfunction; mtDNA damage

DOI:  https://doi.org/10.1152/ajpcell.00389.2021
Cells. 2021 Dec 17. pii: 3569. [Epub ahead of print]10(12):

Mitophagy in Yeast: Molecular Mechanism and Regulation.

Aleksei Innokentev, Tomotake Kanki.

  Mitophagy is a type of autophagy that selectively degrades mitochondria. Mitochondria, known as the "powerhouse of the cell", supply the majority of the energy required by cells. During energy production, mitochondria produce reactive oxygen species (ROS) as byproducts. The ROS damage mitochondria, and the damaged mitochondria further produce mitochondrial ROS. The increased mitochondrial ROS damage cellular components, including mitochondria themselves, and leads to diverse pathologies. Accordingly, it is crucial to eliminate excessive or damaged mitochondria to maintain mitochondrial homeostasis, in which mitophagy is believed to play a major role. Recently, the molecular mechanism and physiological role of mitophagy have been vigorously studied in yeast and mammalian cells. In yeast, Atg32 and Atg43, mitochondrial outer membrane proteins, were identified as mitophagy receptors in budding yeast and fission yeast, respectively. Here we summarize the molecular mechanisms of mitophagy in yeast, as revealed by the analysis of Atg32 and Atg43, and review recent progress in our understanding of mitophagy induction and regulation in yeast.

Keywords:  Atg32; Atg43; autophagy; mitochondria; mitophagy; yeast

DOI:  https://doi.org/10.3390/cells10123569
Cell. 2021 Dec 22. pii: S0092-8674(21)01386-6. [Epub ahead of print]184(26): 6226-6228

Dinner is served, sir: Fighting cancer with the right diet.

Andrés Méndez-Lucas, Mariia Yuneva.

Altered metabolism of tumors offers an opportunity to use metabolic interventions as a therapeutic strategy. Lien et al. demonstrate that understanding how specific diets with different carbohydrate and fat composition affect tumor metabolism is essential in order to use this opportunity efficiently.

DOI: https://doi.org/10.1016/j.cell.2021.11.036
Nat Chem Biol. 2021 Dec 20.

A counter-enzyme complex regulates glutamate metabolism in Bacillus subtilis.

Vijay Jayaraman, D John Lee, Nadav Elad, Shay Vimer, Michal Sharon, James S Fraser, Dan S Tawfik.

Multi-enzyme assemblies composed of metabolic enzymes catalyzing sequential reactions are being increasingly studied. Here, we report the discovery of a 1.6 megadalton multi-enzyme complex from Bacillus subtilis composed of two enzymes catalyzing opposite ('counter-enzymes') rather than sequential reactions: glutamate synthase (GltAB) and glutamate dehydrogenase (GudB), which make and break glutamate, respectively. In vivo and in vitro studies show that the primary role of complex formation is to inhibit the activity of GudB. Using cryo-electron microscopy, we elucidated the structure of the complex and the molecular basis of inhibition of GudB by GltAB. The complex exhibits unusual oscillatory progress curves and is necessary for both planktonic growth, in glutamate-limiting conditions, and for biofilm growth, in glutamate-rich media. The regulation of a key metabolic enzyme by complexing with its counter enzyme may thus enable cell growth under fluctuating glutamate concentrations.

DOI: https://doi.org/10.1038/s41589-021-00919-y
Curr Opin Syst Biol. 2021 Dec;28 None

Understanding circadian regulation of mammalian cell function, protein homeostasis, and metabolism.

Alessandra Stangherlin, Estere Seinkmane, John S O'Neill.

  Circadian rhythms are ∼24 h cycles of organismal and cellular activity ubiquitous to mammalian physiology. A prevailing paradigm suggests that timing information flows linearly from rhythmic transcription via protein abundance changes to drive circadian regulation of cellular function. Challenging this view, recent evidence indicates daily variation in many cellular functions arises through rhythmic post-translational regulation of protein activity. We suggest cellular circadian timing primarily functions to maintain proteome homeostasis rather than perturb it. Indeed, although relevant to timekeeping mechanism, daily rhythms of clock protein abundance may be the exception, not the rule. Informed by insights from yeast and mammalian models, we propose that optimal bioenergetic efficiency results from coupled rhythms in mammalian target of rapamycin complex activity, protein synthesis/turnover, ion transport and protein sequestration, which drive facilitatory rhythms in metabolic flux and substrate utilisation. Such daily consolidation of proteome renewal would account for many aspects of circadian cell biology whilst maintaining osmotic homeostasis.

Keywords:  Biological clock; Cellular function; Circadian rhythm; Homeostasis; Ion transport; Macromolecular crowding; Metabolic cycle; Metabolism; Osmostasis; Protein synthesis; Protein turnover; Respiratory oscillation; TORC

DOI:  https://doi.org/10.1016/j.coisb.2021.100391
Front Cell Dev Biol. 2021 ;9 795685

Protein Quality Control at the Mitochondrial Surface.

Fabian den Brave, Arushi Gupta, Thomas Becker.

  Mitochondria contain two membranes, the outer and inner membrane. The outer membrane fulfills crucial functions for the communication of mitochondria with the cellular environment like exchange of lipids via organelle contact sites, the transport of metabolites and the formation of a signaling platform in apoptosis and innate immunity. The translocase of the outer membrane (TOM complex) forms the entry gate for the vast majority of precursor proteins that are produced on cytosolic ribosomes. Surveillance of the functionality of outer membrane proteins is critical for mitochondrial functions and biogenesis. Quality control mechanisms remove defective and mistargeted proteins from the outer membrane as well as precursor proteins that clog the TOM complex. Selective degradation of single proteins is also an important mode to regulate mitochondrial dynamics and initiation of mitophagy pathways. Whereas inner mitochondrial compartments are equipped with specific proteases, the ubiquitin-proteasome system is a central player in protein surveillance on the mitochondrial surface. In this review, we summarize our current knowledge about the molecular mechanisms that govern quality control of proteins at the outer mitochondrial membrane.

Keywords:  Cdc48; TOM complex; mitochondria; protein quality control; protein sorting

DOI:  https://doi.org/10.3389/fcell.2021.795685
Metabolites. 2021 Nov 29. pii: 811. [Epub ahead of print]11(12):

AMPK-Mediated Metabolic Switching Is High Effective for Phytochemical Levo-Tetrahydropalmatine (l-THP) to Reduce Hepatocellular Carcinoma Tumor Growth.

Xunzhe Yin, Wenbo Li, Jiaxin Zhang, Wenjing Zhao, Huaxing Cai, Chi Zhang, Zuojia Liu, Yan Guo, Jin Wang.

  Targeting cancer cell metabolism has been an attractive approach for cancer treatment. However, the role of metabolic alternation in cancer is still unknown whether it functions as a tumor promoter or suppressor. Applying the cancer gene-metabolism integrative network model, we predict adenosine monophosphate-activated protein kinase (AMPK) to function as a central hub of metabolic landscape switching in specific liver cancer subtypes. For the first time, we demonstrate that the phytochemical levo-tetrahydropalmatine (l-THP), a Corydalis yanhusuo-derived clinical drug, as an AMPK activator via autophagy-mediated metabolic switching could kill the hepatocellular carcinoma HepG2 cells. Mechanistically, l-THP promotes the autophagic response by activating the AMPK-mTOR-ULK1 and the ROS-JNK-ATG cascades and impairing the ERK/AKT signaling. All these processes ultimately synergize to induce the decreased mitochondrial oxidative phosphorylation (OXPHOS) and mitochondrial damage. Notably, silencing AMPK significantly inhibits the autophagic flux and recovers the decreased OXPHOS metabolism, which results in HepG2 resistance to l-THP treatment. More importantly, l-THP potently reduces the growth of xenograft HepG2 tumor in nude mice without affecting other organs. From this perspective, our findings support the conclusion that metabolic change is an alternative approach to influence the development of HCC.

Keywords:  AMPK; autophagy; cancer metabolism; hepatocellular carcinoma; levo-tetrahydropalmatine

DOI:  https://doi.org/10.3390/metabo11120811
Antioxidants (Basel). 2021 Nov 29. pii: 1921. [Epub ahead of print]10(12):

Mitochondrial Redox Regulations and Redox Biology of Mitochondria.

Petr Ježek.

Mitochondria undoubtedly represent a metabolic hub, but also act as a redox hub, controlling cell fate and emanating superoxide/H2O2, which in a regulated form and timing provide redox signaling [...].

DOI: https://doi.org/10.3390/antiox10121921
Biophys J. 2021 Dec 21. pii: S0006-3495(21)03946-1. [Epub ahead of print]

On the Design Principles of Metabolic Flux Sensing.

Christian Euler, Radhakrishnan Mahadevan.

  Metabolism is precisely coordinated, with the goal of balancing fluxes to maintain robust growth. However, coordinating fluxes requires information about rates, which can only be inferred through concentrations. While flux sensitive metabolites have been reported, the design principles underlying such sensing have not been clearly elucidated. Here we use kinetic modelling to show that substrate concentrations of thermodynamically constrained reactions reflect upstream flux and therefore carry information about rates. Then we use untargeted multi-omic data from E. coli and S. cerevisiae to show that the concentrations of some metabolites in central carbon metabolism reflect fluxes as a result of thermodynamic constraints. We then establish, using 37 real concentration-flux relationships across both organisms, that in vivo ΔG∘≥-4 kJ/mol is the threshold above which substrates are likely to be sensitive to upstream flux(es).

Keywords:  design principles; metabolic regulation; metabolism; multi-omics; thermodynamics

DOI:  https://doi.org/10.1016/j.bpj.2021.12.022
Int J Mol Sci. 2021 Dec 16. pii: 13511. [Epub ahead of print]22(24):

Interdependent Regulation of Polycystin Expression Influences Starvation-Induced Autophagy and Cell Death.

Jean-Paul Decuypere, Dorien Van Giel, Peter Janssens, Ke Dong, Stefan Somlo, Yiqiang Cai, Djalila Mekahli, Rudi Vennekens.

  Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by deficiency of polycystin-1 (PC1) or polycystin-2 (PC2). Altered autophagy has recently been implicated in ADPKD progression, but its exact regulation by PC1 and PC2 remains unclear. We therefore investigated cell death and survival during nutritional stress in mouse inner medullary collecting duct cells (mIMCDs), either wild-type (WT) or lacking PC1 (PC1KO) or PC2 (PC2KO), and human urine-derived proximal tubular epithelial cells (PTEC) from early-stage ADPKD patients with PC1 mutations versus healthy individuals. Basal autophagy was enhanced in PC1-deficient cells. Similarly, following starvation, autophagy was enhanced and cell death reduced when PC1 was reduced. Autophagy inhibition reduced cell death resistance in PC1KO mIMCDs to the WT level, implying that PC1 promotes autophagic cell survival. Although PC2 expression was increased in PC1KO mIMCDs, PC2 knockdown did not result in reduced autophagy. PC2KO mIMCDs displayed lower basal autophagy, but more autophagy and less cell death following chronic starvation. This could be reversed by overexpression of PC1 in PC2KO. Together, these findings indicate that PC1 levels are partially coupled to PC2 expression, and determine the transition from renal cell survival to death, leading to enhanced survival of ADPKD cells during nutritional stress.

Keywords:  ADPKD; autophagy; autosomal dominant polycystic kidney disease; cell death; nutrient stress; polycystins

DOI:  https://doi.org/10.3390/ijms222413511
Cell Death Discov. 2021 Dec 20. 7(1): 395

Mitochondrial glutamine metabolism regulates sensitivity of cancer cells after chemotherapy via amphiregulin.

Sunsook Hwang, Seungyeon Yang, Minjoong Kim, Youlim Hong, Byungjoo Kim, Eun Kyung Lee, Seung Min Jeong.

The DNA damage response is essential for sustaining genomic stability and preventing tumorigenesis. However, the fundamental question about the cellular metabolic response to DNA damage remains largely unknown, impeding the development of metabolic interventions that might prevent or treat cancer. Recently, it has been reported that there is a link between cell metabolism and DNA damage response, by repression of glutamine (Gln) entry into mitochondria to support cell cycle arrest and DNA repair. Here, we show that mitochondrial Gln metabolism is a crucial regulator of DNA damage-induced cell death. Mechanistically, inhibition of glutaminase (GLS), the first enzyme for Gln anaplerosis, sensitizes cancer cells to DNA damage by inducing amphiregulin (AREG) that promotes apoptotic cell death. GLS inhibition increases reactive oxygen species production, leading to transcriptional activation of AREG through Max-like protein X (MLX) transcription factor. Moreover, suppression of mitochondrial Gln metabolism results in markedly increased cell death after chemotherapy in vitro and in vivo. The essentiality of this molecular pathway in DNA damage-induced cell death may provide novel metabolic interventions for cancer therapy.

DOI: https://doi.org/10.1038/s41420-021-00792-7
Cancer Metastasis Rev. 2021 Dec 21.

Extracellular citrate and metabolic adaptations of cancer cells.

E Kenneth Parkinson, Jerzy Adamski, Grit Zahn, Andreas Gaumann, Fabian Flores-Borja, Christine Ziegler, Maria E Mycielska.

  It is well established that cancer cells acquire energy via the Warburg effect and oxidative phosphorylation. Citrate is considered to play a crucial role in cancer metabolism by virtue of its production in the reverse Krebs cycle from glutamine. Here, we review the evidence that extracellular citrate is one of the key metabolites of the metabolic pathways present in cancer cells. We review the different mechanisms by which pathways involved in keeping redox balance respond to the need of intracellular citrate synthesis under different extracellular metabolic conditions. In this context, we further discuss the hypothesis that extracellular citrate plays a role in switching between oxidative phosphorylation and the Warburg effect while citrate uptake enhances metastatic activities and therapy resistance. We also present the possibility that organs rich in citrate such as the liver, brain and bones might form a perfect niche for the secondary tumour growth and improve survival of colonising cancer cells. Consistently, metabolic support provided by cancer-associated and senescent cells is also discussed. Finally, we highlight evidence on the role of citrate on immune cells and its potential to modulate the biological functions of pro- and anti-tumour immune cells in the tumour microenvironment. Collectively, we review intriguing evidence supporting the potential role of extracellular citrate in the regulation of the overall cancer metabolism and metastatic activity.

Keywords:  Cancer-associated cells; Citrate; OXPHOS; Redox; Senescence; Warburg effect

DOI:  https://doi.org/10.1007/s10555-021-10007-1
Cancer Biol Med. 2021 Dec 22. pii: j.issn.2095-3941.2021.0461. [Epub ahead of print]

Cancer metabolism and dietary interventions.

Lin Qian, Fan Zhang, Miao Yin, Qunying Lei.

  Metabolic remodeling is a key feature of cancer development. Knowledge of cancer metabolism has greatly expanded since the first observation of abnormal metabolism in cancer cells, the so-called Warburg effect. Malignant cells tend to modify cellular metabolism to favor specialized fermentation over the aerobic respiration usually used by most normal cells. Thus, targeted cancer therapies based on reprogramming nutrient or metabolite metabolism have received substantial attention both conceptually and in clinical practice. In particular, the management of nutrient availability is becoming more attractive in cancer treatment. In this review, we discuss recent findings on tumor metabolism and potential dietary interventions based on the specific characteristics of tumor metabolism. First, we present a comprehensive overview of changes in macronutrient metabolism. Carbohydrates, amino acids, and lipids, are rewired in the cancer microenvironment individually or systematically. Second, we summarize recent progress in cancer interventions applying different types of diets and specific nutrient restrictions in pre-clinical research or clinical trials.

Keywords:  Cancer metabolism; amino acid; carbohydrate; diet intervention; lipid

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2021.0461
Dev Cell. 2021 Dec 20. pii: S1534-5807(21)00992-8. [Epub ahead of print]56(24): 3307-3308

Clone competition as a mechanism to reduce tumor formation.

Amelia Acha-Sagredo, Ilaria Malanchi, Francesca D Ciccarelli.

With age, clones carrying somatic mutations in well-known cancer driver genes progressively populate adult tissues, yet cancer transformation is rare. In a recent issue of Nature, Colom et al. showed that competition between mutated clones with different fitness could act as a tumor-protective mechanism.

DOI: https://doi.org/10.1016/j.devcel.2021.12.003
JCI Insight. 2021 Dec 23. pii: e153526. [Epub ahead of print]

Tissue metabolites in diffuse glioma and their modulations by IDH1 mutation, histology and treatment.

Christoph Trautwein, Laimdota Zizmare, Irina Mäurer, Benjamin Bender, Björn Bayer, Ulrike Ernemann, Marcos Tatagiba, Stefan J Grau, Bernd J Pichler, Marco Skardelly, Ghazaleh Tabatabai.

  The discovery of the oncometabolite 2-hydroxyglutarate in isocitrate dehydrogenase (IDH)1-mutated tumor entities affirmed the role of metabolism in cancer. Yet, large databases with tissue metabolites that are modulated by IDH1 mutation remain an area of development. Here, we present an unprecedented and valuable resource for tissue metabolites in diffuse glioma and their modulations by IDH1 mutation, histology and tumor treatments in 101 tissue samples from 73 diffuse glioma patients (24 astrocytoma, 17 oligodendroglioma, 32 glioblastoma), investigated by NMR-based metabolomics and supported by RNA sequencing. We discovered comparison-specific metabolites and pathways modulated by IDH1 ("IDH1 mutation status cohort") and tumor entity. The "Longitudinal investigation cohort" provides metabolic profiles of untreated and corresponding treated glioma samples at first progression. Most interestingly, univariate and multivariate cox regressions and Kaplan Meier analyses revealed that tissue metabolites correlate with progression-free and overall survival. Thus, this study introduces novel candidate prognostic and surrogate metabolite biomarkers for future prospective clinical studies aiming at further refining patient stratification in diffuse glioma. Furthermore, our data will facilitate the generation of so far unanticipated hypotheses for experimental studies to advance our molecular understanding of glioma biology.

Keywords:  Brain cancer; Oncology

DOI:  https://doi.org/10.1172/jci.insight.153526
Urol Case Rep. 2022 Jan;40 101950

Management of SHDB positive patient with metastatic bilateral giant retroperitoneal paragangliomas.

David Strauss, Andres Correa, Yulan Gong, Andreas Karachristos, Alexander Kutikov.

  Paragangliomas are rare neuroendocrine tumors that can vary in size and metabolic activity. We report a case of giant bilateral malignant retroperitoneal paragangliomas (PGL) in a patient with germline succinate dehydrogenase B (SDHB) mutation. This patient, who presented in an emaciated and debilitated state, was managed with adrenergic blockade followed by radical primary surgery. After being metabolically and radiographically disease free for 4 years, he underwent salvage resection for recurrent retroperitoneal disease and palliative radiation to a site of solidary vertebral metastasis. We review incidence and prognosis of metastatic PGL.

Keywords:  Giant paraganglioma; Paraganglioma, (PGL); Retroperitoneal; Succinate dehydrogenase B subunit, (SDHB); Succinate dehydrogenase mutation; Succinate dehydrogenase, (SDH)

DOI:  https://doi.org/10.1016/j.eucr.2021.101950
Biology (Basel). 2021 Dec 03. pii: 1267. [Epub ahead of print]10(12):

Breast Cancer Cell Subtypes Display Different Metabolic Phenotypes That Correlate with Their Clinical Classification.

Consuelo Ripoll, Mar Roldan, Maria J Ruedas-Rama, Angel Orte, Miguel Martin.

  Metabolic reprogramming of cancer cells represents an orchestrated network of evolving molecular and functional adaptations during oncogenic progression. In particular, how metabolic reprogramming is orchestrated in breast cancer and its decisive role in the oncogenic process and tumor evolving adaptations are well consolidated at the molecular level. Nevertheless, potential correlations between functional metabolic features and breast cancer clinical classification still represent issues that have not been fully studied to date. Accordingly, we aimed to investigate whether breast cancer cell models representative of each clinical subtype might display different metabolic phenotypes that correlate with current clinical classifications. In the present work, functional metabolic profiling was performed for breast cancer cell models representative of each clinical subtype based on the combination of enzyme inhibitors for key metabolic pathways, and isotope-labeled tracing dynamic analysis. The results indicated the main metabolic phenotypes, so-called 'metabophenotypes', in terms of their dependency on glycolytic metabolism or their reliance on mitochondrial oxidative metabolism. The results showed that breast cancer cell subtypes display different metabophenotypes. Importantly, these metabophenotypes are clearly correlated with the current clinical classifications.

Keywords:  breast cancer; metabolic profiling; metabolic reprogramming; tumor metabolism

DOI:  https://doi.org/10.3390/biology10121267
JCI Insight. 2021 Dec 22. pii: e154089. [Epub ahead of print]6(24):

Metabolic reprogramming during hyperammonemia targets mitochondrial function and postmitotic senescence.

Avinash Kumar, Nicole Welch, Saurabh Mishra, Annette Bellar, Rafaella Nasciemento Silva, Ling Li, Shashi Shekhar Singh, Mary Sharkoff, Alexis Kerr, Aruna Kumar Chelluboyina, Jinendiran Sekar, Amy H Attaway, Charles Hoppel, Belinda Willard, Gangarao Davuluri, Srinivasan Dasarathy.

  Ammonia is a cytotoxic metabolite with pleiotropic molecular and metabolic effects, including senescence induction. During dysregulated ammonia metabolism, which occurs in chronic diseases, skeletal muscle becomes a major organ for nonhepatocyte ammonia uptake. Muscle ammonia disposal occurs in mitochondria via cataplerosis of critical intermediary metabolite α-ketoglutarate, a senescence-ameliorating molecule. Untargeted and mitochondrially targeted data were analyzed by multiomics approaches. These analyses were validated experimentally to dissect the specific mitochondrial oxidative defects and functional consequences, including senescence. Responses to ammonia lowering in myotubes and in hyperammonemic portacaval anastomosis rat muscle were studied. Whole-cell transcriptomics integrated with whole-cell, mitochondrial, and tissue proteomics showed distinct temporal clusters of responses with enrichment of oxidative dysfunction and senescence-related pathways/proteins during hyperammonemia and after ammonia withdrawal. Functional and metabolic studies showed defects in electron transport chain complexes I, III, and IV; loss of supercomplex assembly; decreased ATP synthesis; increased free radical generation with oxidative modification of proteins/lipids; and senescence-associated molecular phenotype-increased β-galactosidase activity and expression of p16INK, p21, and p53. These perturbations were partially reversed by ammonia lowering. Dysregulated ammonia metabolism caused reversible mitochondrial dysfunction by transcriptional and translational perturbations in multiple pathways with a distinct skeletal muscle senescence-associated molecular phenotype.

Keywords:  Cell Biology; Cellular senescence; Hepatology; Mitochondria; Skeletal muscle

DOI:  https://doi.org/10.1172/jci.insight.154089
Cell Rep. 2021 Dec 21. pii: S2211-1247(21)01629-6. [Epub ahead of print]37(12): 110133

Astroglial ER-mitochondria calcium transfer mediates endocannabinoid-dependent synaptic integration.

Roman Serrat, Ana Covelo, Vladimir Kouskoff, Sebastien Delcasso, Andrea Ruiz-Calvo, Nicolas Chenouard, Carol Stella, Corinne Blancard, Benedicte Salin, Francisca Julio-Kalajzić, Astrid Cannich, Federico Massa, Marjorie Varilh, Severine Deforges, Laurie M Robin, Diego De Stefani, Arnau Busquets-Garcia, Frederic Gambino, Anna Beyeler, Sandrine Pouvreau, Giovanni Marsicano.

  Intracellular calcium signaling underlies the astroglial control of synaptic transmission and plasticity. Mitochondria-endoplasmic reticulum contacts (MERCs) are key determinants of calcium dynamics, but their functional impact on astroglial regulation of brain information processing is unexplored. We found that the activation of astrocyte mitochondrial-associated type-1 cannabinoid (mtCB1) receptors determines MERC-dependent intracellular calcium signaling and synaptic integration. The stimulation of mtCB1 receptors promotes calcium transfer from the endoplasmic reticulum to mitochondria through a specific molecular cascade, involving the mitochondrial calcium uniporter (MCU). Physiologically, mtCB1-dependent mitochondrial calcium uptake determines the dynamics of cytosolic calcium events in astrocytes upon endocannabinoid mobilization. Accordingly, electrophysiological recordings in hippocampal slices showed that conditional genetic exclusion of mtCB1 receptors or dominant-negative MCU expression in astrocytes blocks lateral synaptic potentiation, through which astrocytes integrate the activity of distant synapses. Altogether, these data reveal an endocannabinoid link between astroglial MERCs and the regulation of brain network functions.

Keywords:  CB1; MERCs; astrocytes; calcium; cannabinoid; lateral synaptic potentiation; mitochondria

DOI:  https://doi.org/10.1016/j.celrep.2021.110133
iScience. 2021 Dec 17. 24(12): 103497

Mitochondrial complex I inhibitors suppress tumor growth through concomitant acidification of the intra- and extracellular environment.

Junjiro Yoshida, Tomokazu Ohishi, Hikaru Abe, Shun-Ichi Ohba, Hiroyuki Inoue, Ihomi Usami, Masahide Amemiya, Raphael Oriez, Chiharu Sakashita, Shingo Dan, Minoru Sugawara, Tokuichi Kawaguchi, Junko Ueno, Yuko Asano, Ami Ikeda, Manabu Takamatsu, Gulanbar Amori, Yasumitsu Kondoh, Kaori Honda, Hiroyuki Osada, Tetsuo Noda, Takumi Watanabe, Takao Shimizu, Masakatsu Shibasaki, Manabu Kawada.

  The disruption of the tumor microenvironment (TME) is a promising anti-cancer strategy, but its effective targeting for solid tumors remains unknown. Here, we investigated the anti-cancer activity of the mitochondrial complex I inhibitor intervenolin (ITV), which modulates the TME independent of energy depletion. By modulating lactate metabolism, ITV induced the concomitant acidification of the intra- and extracellular environment, which synergistically suppressed S6K1 activity in cancer cells through protein phosphatase-2A-mediated dephosphorylation via G-protein-coupled receptor(s). Other complex I inhibitors including metformin and rotenone were also found to exert the same effect through an energy depletion-independent manner as ITV. In mouse and patient-derived xenograft models, ITV was found to suppress tumor growth and its mode of action was further confirmed. The TME is usually acidic owing to glycolytic cancer cell metabolism, and this condition is more susceptible to complex I inhibitors. Thus, we have demonstrated a potential treatment strategy for solid tumors.

Keywords:  Cancer; Cell biology; Microenvironment

DOI:  https://doi.org/10.1016/j.isci.2021.103497
Nat Commun. 2021 Dec 21. 12(1): 7362

Lipid droplet availability affects neural stem/progenitor cell metabolism and proliferation.

Mergim Ramosaj, Sofia Madsen, Vanille Maillard, Valentina Scandella, Daniel Sudria-Lopez, Naoya Yuizumi, Ludovic Telley, Marlen Knobloch.

Neural stem/progenitor cells (NSPCs) generate new neurons throughout adulthood. However, the underlying regulatory processes are still not fully understood. Lipid metabolism plays an important role in regulating NSPC activity: build-up of lipids is crucial for NSPC proliferation, whereas break-down of lipids has been shown to regulate NSPC quiescence. Despite their central role for cellular lipid metabolism, the role of lipid droplets (LDs), the lipid storing organelles, in NSPCs remains underexplored. Here we show that LDs are highly abundant in adult mouse NSPCs, and that LD accumulation is significantly altered upon fate changes such as quiescence and differentiation. NSPC proliferation is influenced by the number of LDs, inhibition of LD build-up, breakdown or usage, and the asymmetric inheritance of LDs during mitosis. Furthermore, high LD-containing NSPCs have increased metabolic activity and capacity, but do not suffer from increased oxidative damage. Together, these data indicate an instructive role for LDs in driving NSPC behaviour.

DOI: https://doi.org/10.1038/s41467-021-27365-7
Cell. 2021 Dec 22. pii: S0092-8674(21)01375-1. [Epub ahead of print]184(26): 6217-6221

Using virtual interviewing to create a more accessible hybrid academic job market.

Christina M Termini, Florentine U N Rutaganira, Caroline B Palavicino-Maggio, Chelsey C Spriggs, Chantell S Evans, Melanie R McReynolds.

Virtual interviewing has become ubiquitous with the academic job market. Here, we highlight the best practices for candidates and departments to consider when using virtual interviewing. We propose how virtual interviews can be leveraged and adapted for hybrid academic job searches combining virtual and in-person activities in a post-pandemic world.

DOI: https://doi.org/10.1016/j.cell.2021.11.027
EMBO J. 2021 Dec 21. e108690

BCL-2-family protein tBID can act as a BAX-like effector of apoptosis.

Hector Flores-Romero, Lisa Hohorst, Malina John, Marie-Christine Albert, Louise E King, Laura Beckmann, Tamas Szabo, Vanessa Hertlein, Xu Luo, Andreas Villunger, Lukas P Frenzel, Hamid Kashkar, Ana J Garcia-Saez.

  During apoptosis, the BCL-2-family protein tBID promotes mitochondrial permeabilization by activating BAX and BAK and by blocking anti-apoptotic BCL-2 members. Here, we report that tBID can also mediate mitochondrial permeabilization by itself, resulting in release of cytochrome c and mitochondrial DNA, caspase activation and apoptosis even in absence of BAX and BAK. This previously unrecognized activity of tBID depends on helix 6, homologous to the pore-forming regions of BAX and BAK, and can be blocked by pro-survival BCL-2 proteins. Importantly, tBID-mediated mitochondrial permeabilization independent of BAX and BAK is physiologically relevant for SMAC release in the immune response against Shigella infection. Furthermore, it can be exploited to kill leukaemia cells with acquired venetoclax resistance due to lack of active BAX and BAK. Our findings define tBID as an effector of mitochondrial permeabilization in apoptosis and provide a new paradigm for BCL-2 proteins, with implications for anti-bacterial immunity and cancer therapy.

Keywords:  BCL-2 proteins; apoptosis; mitochondrial permeabilization; pore formation

DOI:  https://doi.org/10.15252/embj.2021108690
Int J Cancer. 2021 Dec 18.

Complexity against current cancer research - are we on the wrong track?

Yasenya Kasikci, Hinrich Gronemeyer.

  Cancer genetics has led to major discoveries, including proto-oncogene and tumor-suppressor concepts, and cancer genomics generated concepts like driver and passenger genes, revealed tumor heterogeneity and clonal evolution. Reconstructing trajectories of tumorigenesis using spatial and single-cell genomics is possible. Patient stratification and prognostic parameters have been improved. Yet, despite these advances, successful translation into targeted therapies has been scarce and mostly limited to kinase inhibitors. Here, we argue that current cancer research may be on the wrong track, by considering cancer more as a "monogenic" disease, trying to extract common information from thousands of patients, while not properly considering complexity and individual diversity. We suggest to empower a systems cancer approach which reconstructs the information network that has been altered by the tumorigenic events, to analyze hierarchies and predict (druggable) key nodes that could interfere with/block the aberrant information transfer. We also argue that the inter-individual variability between patients of similar cohorts is too high to extract common polygenic network information from large numbers of patients and argue in favor of an individualized approach. The analysis we propose would require a structured multinational and multidisciplinary effort, in which clinicians, and cancer, developmental, cell and computational biologists together with mathematicians and informaticians develop dynamic regulatory networks which integrate the entire information transfer in and between cells and organs in (patho)physiological conditions, revealing hierarchies and available drugs to interfere with key regulators. Based on this blueprint, the altered information transfer in individual cancers could be modeled and possible targeted (combo)therapies proposed. This article is protected by copyright. All rights reserved.

Keywords:  Conceptual problems in cancer genomics; complexity challenge; information transfer; integrated network analysis

DOI:  https://doi.org/10.1002/ijc.33912
Nature. 2021 Dec 22.

Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer.

Lanbo Xiao, Abhijit Parolia, Yuanyuan Qiao, Pushpinder Bawa, Sanjana Eyunni, Rahul Mannan, Sandra E Carson, Yu Chang, Xiaoju Wang, Yuping Zhang, Josh N Vo, Steven Kregel, Stephanie A Simko, Andrew D Delekta, Mustapha Jaber, Heng Zheng, Ingrid J Apel, Lisa McMurry, Fengyun Su, Rui Wang, Sylvia Zelenka-Wang, Sanjita Sasmal, Leena Khare, Subhendu Mukherjee, Chandrasekhar Abbineni, Kiran Aithal, Mital S Bhakta, Jay Ghurye, Xuhong Cao, Nora M Navone, Alexey I Nesvizhskii, Rohit Mehra, Ulka Vaishampayan, Marco Blanchette, Yuzhuo Wang, Susanta Samajdar, Murali Ramachandra, Arul M Chinnaiyan.

The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling1 and is altered in over 20% of cancers2,3. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.

DOI: https://doi.org/10.1038/s41586-021-04246-z
Int J Mol Sci. 2021 Dec 20. pii: 13668. [Epub ahead of print]22(24):

Ionic Regulation of T-Cell Function and Anti-Tumour Immunity.

Pierpaolo Ginefra, Helen Carrasco Hope, Mattia Spagna, Alessandra Zecchillo, Nicola Vannini.

  The capacity of T cells to identify and kill cancer cells has become a central pillar of immune-based cancer therapies. However, T cells are characterized by a dysfunctional state in most tumours. A major obstacle for proper T-cell function is the metabolic constraints posed by the tumour microenvironment (TME). In the TME, T cells compete with cancer cells for macronutrients (sugar, proteins, and lipid) and micronutrients (vitamins and minerals/ions). While the role of macronutrients in T-cell activation and function is well characterized, the contribution of micronutrients and especially ions in anti-tumour T-cell activities is still under investigation. Notably, ions are important for most of the signalling pathways regulating T-cell anti-tumour function. In this review, we discuss the role of six biologically relevant ions in T-cell function and in anti-tumour immunity, elucidating potential strategies to adopt to improve immunotherapy via modulation of ion metabolism.

Keywords:  T cell; immunomodulation; ions; nutrient competition; tumour microenvironment

DOI:  https://doi.org/10.3390/ijms222413668
Trends Immunol. 2022 Jan;pii: S1471-4906(21)00243-X. [Epub ahead of print]43(1): 78-92

The cholesterol pathway: impact on immunity and cancer.

Ryan J King, Pankaj K Singh, Kamiya Mehla.

  Cholesterol is a multifaceted metabolite that is known to modulate processes in cancer, atherosclerosis, and autoimmunity. A common denominator between these diseases appears to be the immune system, in which many cholesterol-associated metabolites impact both adaptive and innate immunity. Many cancers display altered cholesterol metabolism, and recent studies demonstrate that manipulating systemic cholesterol metabolism may be useful in improving immunotherapy responses. However, cholesterol can have both proinflammatory and anti-inflammatory roles in mammals, acting via multiple immune cell types, and depending on context. Gaining mechanistic insights into various cholesterol-related metabolites can improve our understanding of their functions and extensive effects on the immune system, and ideally will inform the design of future therapeutic strategies against cancer and/or other pathologies.

Keywords:  LXR; cancer; cholesterol; immune; oxysterol; statins

DOI:  https://doi.org/10.1016/j.it.2021.11.007
Int J Mol Sci. 2021 Dec 20. pii: 13666. [Epub ahead of print]22(24):

Glycolysis under Circadian Control.

Jana Zlacká, Michal Zeman.

  Glycolysis is considered a main metabolic pathway in highly proliferative cells, including endothelial, epithelial, immune, and cancer cells. Although oxidative phosphorylation (OXPHOS) is more efficient in ATP production per mole of glucose, proliferative cells rely predominantly on aerobic glycolysis, which generates ATP faster compared to OXPHOS and provides anabolic substrates to support cell proliferation and migration. Cellular metabolism, including glucose metabolism, is under strong circadian control. Circadian clocks control a wide array of metabolic processes, including glycolysis, which exhibits a distinct circadian pattern. In this review, we discuss circadian regulations during metabolic reprogramming and key steps of glycolysis in activated, highly proliferative cells. We suggest that the inhibition of metabolic reprogramming in the circadian manner can provide some advantages in the inhibition of oxidative glycolysis and a chronopharmacological approach is a promising way to treat diseases associated with up-regulated glycolysis.

Keywords:  circadian; clock genes; glycolysis; metabolic reprogramming; oxidative phosphorylation

DOI:  https://doi.org/10.3390/ijms222413666