bims-camemi 2019-08-11 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2019‒08‒11
37 papers selected by
Christian Frezza,

Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses.
Mitochondria-hubs for regulating cellular biochemistry: emerging concepts and networks.
Monocarboxylate transporters in cancer.
Targeting pyrimidine synthesis accentuates molecular therapy response in glioblastoma stem cells.
Mitochondria Plasticity in Cell Fate Regulation.
Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation.
The emerging role of the mitochondrial fatty-acid synthase (mtFASII) in the regulation of energy metabolism.
Acyl-CoA-Binding Protein Fuels Gliomagenesis.
IDH2 deficiency impairs cutaneous wound healing via ROS-dependent apoptosis.
Succinate in ischemia: where does it come from?
Mitochondrial translocation of cyclin C stimulates intrinsic apoptosis through Bax recruitment.
CDK4 regulates lysosomal function and mTORC1 activation to promote cancer cell survival.
Opposing Functions of Interferon Coordinate Adaptive and Innate Immune Responses to Cancer Immune Checkpoint Blockade.
Fatty Acid Metabolites Combine with Reduced β Oxidation to Activate Th17 Inflammation in Human Type 2 Diabetes.
Pyruvate Kinase Regulates the Pentose-Phosphate Pathway in Response to Hypoxia in Mycobacterium tuberculosis.
Hyperoxidation of mitochondrial peroxiredoxin limits H2 O2 -induced cell death in yeast.
Functional reprogramming of regulatory T cells in the absence of Foxp3.
Inhibition of phosphoenolpyruvate carboxykinase blocks lactate utilization and impairs tumor growth in colorectal cancer.
EGFR Pathway Links Amino Acid Levels and Induction of Macropinocytosis.
Mitofusin 2 Is Essential for IP3-Mediated SR/Mitochondria Metabolic Feedback in Ventricular Myocytes.
Functional analysis of coiled-coil domains of MCU in mitochondrial calcium uptake.
Isoform-Specific Destabilization of the Active Site Reveals a Molecular Mechanism of Intrinsic Activation of KRas G13D.
BORIS promotes chromatin regulatory interactions in treatment-resistant cancer cells.
Mitochondrial DNA Inheritance in Humans: Mix, Match, and Survival of the Fittest.
Rerouting metabolism to activate macrophages.
MISTERMINATE Mechanistically Links Mitochondrial Dysfunction with Proteostasis Failure.
The Oncogenic Action of NRF2 Depends on De-glycation by Fructosamine-3-Kinase.
Sex Differences in Intestinal Carbohydrate Metabolism Promote Food Intake and Sperm Maturation.
European mtDNA Variants Are Associated With Differential Responses to Cisplatin, an Anticancer Drug: Implications for Drug Resistance and Side Effects.
Dual peroxisome-proliferator-activated-receptor-α/γ activation inhibits SIRT1-PGC1α axis and causes cardiac dysfunction.
Oxidative phosphorylation as a potential therapeutic target for cancer therapy.
Mutant IDH sensitizes gliomas to endoplasmic reticulum stress and triggers apoptosis by MicroRNA183-mediated inhibition of Semaphorin 3E.
Lin28 enhances de novo fatty acid synthesis to promote cancer progression via SREBP-1.
Knowing When to Let Go: Lysosomes Regulate Inter-Mitochondrial Tethering.
Glucose dysregulation in pre-clinical Alzheimer's disease.
O-GlcNAcylated c-Jun antagonizes ferroptosis via inhibiting GSH synthesis in liver cancer.
Matching tumours to treatment buys time for those with a deadly cancer.

Nat Immunol. 2019 Aug 05.

Glycerol phosphate shuttle enzyme GPD2 regulates macrophage inflammatory responses.

P Kent Langston, Aya Nambu, Jonathan Jung, Munehiko Shibata, H Ibrahim Aksoylar, Jiahui Lei, Peining Xu, Mary T Doan, Helen Jiang, Michael R MacArthur, Xia Gao, Yong Kong, Edward T Chouchani, Jason W Locasale, Nathaniel W Synder, Tiffany Horng.

Macrophages are activated during microbial infection to coordinate inflammatory responses and host defense. Here we find that in macrophages activated by bacterial lipopolysaccharide (LPS), mitochondrial glycerol 3-phosphate dehydrogenase (GPD2) regulates glucose oxidation to drive inflammatory responses. GPD2, a component of the glycerol phosphate shuttle, boosts glucose oxidation to fuel the production of acetyl coenzyme A, acetylation of histones and induction of genes encoding inflammatory mediators. While acute exposure to LPS drives macrophage activation, prolonged exposure to LPS triggers tolerance to LPS, where macrophages induce immunosuppression to limit the detrimental effects of sustained inflammation. The shift in the inflammatory response is modulated by GPD2, which coordinates a shutdown of oxidative metabolism; this limits the availability of acetyl coenzyme A for histone acetylation at genes encoding inflammatory mediators and thus contributes to the suppression of inflammatory responses. Therefore, GPD2 and the glycerol phosphate shuttle integrate the extent of microbial stimulation with glucose oxidation to balance the beneficial and detrimental effects of the inflammatory response.

DOI: https://doi.org/10.1038/s41590-019-0453-7
Open Biol. 2019 Aug 30. 9(8): 190126

Mitochondria-hubs for regulating cellular biochemistry: emerging concepts and networks.

Alexander J Anderson, Thomas D Jackson, David A Stroud, Diana Stojanovski.

  Mitochondria are iconic structures in biochemistry and cell biology, traditionally referred to as the powerhouse of the cell due to a central role in energy production. However, modern-day mitochondria are recognized as key players in eukaryotic cell biology and are known to regulate crucial cellular processes, including calcium signalling, cell metabolism and cell death, to name a few. In this review, we will discuss foundational knowledge in mitochondrial biology and provide snapshots of recent advances that showcase how mitochondrial function regulates other cellular responses.

Keywords:  metabolism; mitochondria; mitochondrial biogenesis

DOI:  https://doi.org/10.1098/rsob.190126
Mol Metab. 2019 Jul 27. pii: S2212-8778(19)30403-X. [Epub ahead of print]

Monocarboxylate transporters in cancer.

Valéry L Payen, Erica Mina, Vincent F Van Hée, Paolo E Porporato, Pierre Sonveaux.

  BACKGROUND: Tumors are highly plastic metabolic entities composed of cancer and host cells that can adopt different metabolic phenotypes. For energy production, cancer cells may use 4 main fuels that are shuttled in 5 different metabolic pathways. Glucose fuels glycolysis that can be coupled to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in oxidative cancer cells or to lactic fermentation in proliferating and in hypoxic cancer cells. Lipids fuel lipolysis, glutamine fuels glutaminolysis, and lactate fuels the oxidative pathway of lactate, all of which are coupled to the TCA cycle and OXPHOS for energy production. This review focuses on the latter metabolic pathway.SCOPE OF REVIEW: Lactate, which is prominently produced by glycolytic cells in tumors, was only recently recognized as a major fuel for oxidative cancer cells and as a signaling agent. Its exchanges across membranes are gated by monocarboxylate transporters MCT1-4. This review summarizes the current knowledge about MCT structure, regulation and functions in cancer, with a specific focus on lactate metabolism, lactate-induced angiogenesis and MCT-dependent cancer metastasis. It also describes lactate signaling via cell surface lactate receptor GPR81.
MAJOR CONCLUSIONS: Lactate and MCTs, especially MCT1 and MCT4, are important contributors to tumor aggressiveness. Analyses of MCT-deficient (MCT+/- and MCT-/-) animals and (MCT-mutated) humans indicate that they are druggable, with MCT1 inhibitors being in advanced development phase and MCT4 inhibitors still in the discovery phase. Imaging lactate fluxes non-invasively using a lactate tracer for positron emission tomography would further help to identify responders to the treatments.

Keywords:  Angiogenesis; Cancer metabolism; GPR81; Metabolic symbiosis; Metastasis; Monocarboxylate transporters (MCTs)

DOI:  https://doi.org/10.1016/j.molmet.2019.07.006
Sci Transl Med. 2019 Aug 07. pii: eaau4972. [Epub ahead of print]11(504):

Targeting pyrimidine synthesis accentuates molecular therapy response in glioblastoma stem cells.

Xiuxing Wang, Kailin Yang, Qiulian Wu, Leo J Y Kim, Andrew R Morton, Ryan C Gimple, Briana C Prager, Yu Shi, Wenchao Zhou, Shruti Bhargava, Zhe Zhu, Li Jiang, Weiwei Tao, Zhixin Qiu, Linjie Zhao, Guoxing Zhang, Xiqing Li, Sameer Agnihotri, Paul S Mischel, Stephen C Mack, Shideng Bao, Jeremy N Rich.

Glioblastoma stem cells (GSCs) reprogram glucose metabolism by hijacking high-affinity glucose uptake to survive in a nutritionally dynamic microenvironment. Here, we trace metabolic aberrations in GSCs to link core genetic mutations in glioblastoma to dependency on de novo pyrimidine synthesis. Targeting the pyrimidine synthetic rate-limiting step enzyme carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD) or the critical downstream enzyme dihydroorotate dehydrogenase (DHODH) inhibited GSC survival, self-renewal, and in vivo tumor initiation through the depletion of the pyrimidine nucleotide supply in rodent models. Mutations in EGFR or PTEN generated distinct CAD phosphorylation patterns to activate carbon influx through pyrimidine synthesis. Simultaneous abrogation of tumor-specific driver mutations and DHODH activity with clinically approved inhibitors demonstrated sustained inhibition of metabolic activity of pyrimidine synthesis and GSC tumorigenic capacity in vitro. Higher expression of pyrimidine synthesis genes portends poor prognosis of patients with glioblastoma. Collectively, our results demonstrate a therapeutic approach of precision medicine through targeting the nexus between driver mutations and metabolic reprogramming in cancer stem cells.

DOI: https://doi.org/10.1126/scitranslmed.aau4972
J Biol Chem. 2019 08 05. pii: jbc.REV118.000828. [Epub ahead of print]

Mitochondria Plasticity in Cell Fate Regulation.

Amir Bahat, Atan Gross.

  Mitochondria are considered highly plastic organelles. This plasticity enables the mitochondria to undergo morphological and functional changes in response to cellular demands. Stem cells also need to remain functionally plastic, i.e.to have the ability to "decide" whether to remain quiescent or to undergo activation upon signaling cues in order to support tissue function and homeostasis. Mitochondrial plasticity is thought to enable this reshaping of stem cell functions, integrating signaling cues with stem cell outcomes. Indeed, recent evidence highlights the crucial role of maintaining mitochondrial plasticity for stem cell biology. For example, tricarboxylic acid (TCA) cycle metabolites generated and metabolized in the mitochondria serve as cofactors for epigenetic enzymes, thereby coupling mitochondrial metabolism and transcriptional regulation. Another layer of mitochondrial plasticity has emerged, pointing toward mitochondrial dynamics in regulating stem cell fate decisions. Imposing imbalanced mitochondrial dynamics by manipulating the expression levels of the key molecular regulators of this process influences cellular outcomes by changing the nuclear transcriptional program. Moreover, reactive oxygen species (ROS) have also been shown to play an important role in regulating transcriptional profiles in stem cells. In this review, we focus on recent findings demonstrating that mitochondria are essential regulators of stem cell activation and fate decisions. We also discuss the suggested mechanisms and alternative routes for mitochondria-to-nucleus communications.

Keywords:  epigenetics; metabolism; mitochondria; nucleus; stem cells

DOI:  https://doi.org/10.1074/jbc.REV118.000828
J Clin Invest. 2019 Aug 08. pii: 125022. [Epub ahead of print]130

Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation.

W Brian Dalton, Eric Helmenstine, Noel Walsh, Lukasz P Gondek, Dhanashree S Kelkar, Abigail Read, Rachael Natrajan, Eric S Christenson, Barbara Roman, Samarjit Das, Liang Zhao, Robert D Leone, Daniel Shinn, Taylor Groginski, Anil K Madugundu, Arun Patil, Daniel J Zabransky, Arielle Medford, Justin Lee, Alex J Cole, Marc Rosen, Maya Thakar, Alexander Ambinder, Joshua Donaldson, Amy E DeZern, Karen Cravero, David Chu, Rafael Madero-Marroquin, Akhilesh Pandey, Paula J Hurley, Josh Lauring, Ben Park.

  Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of SF3B1MUT xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against SF3B1MUT cancers.

Keywords:  Amino acid metabolism; Cancer; Metabolism; Oncology

DOI:  https://doi.org/10.1172/JCI125022
Biochim Biophys Acta Mol Cell Biol Lipids. 2019 Jul 31. pii: S1388-1981(19)30134-9. [Epub ahead of print]

The emerging role of the mitochondrial fatty-acid synthase (mtFASII) in the regulation of energy metabolism.

Zeinab Wehbe, Sidney Behringer, Khaled Alatibi, David Watkins, David Rosenblatt, Ute Spiekerkoetter, Sara Tucci.

  Malonyl-CoA synthetase (ACSF3) catalyzes the first step of the mitochondrial fatty acid biosynthesis (mtFASII). Mutations in ACSF3 cause CMAMMA a rare inborn error of metabolism. The clinical phenotype is very heterogeneous, with some patients presenting with neurologic manifestations. In some children, presenting symptoms such as coma, ketoacidosis and hypoglycemia are suggestive of an intermediary metabolic disorder. The overall pathophysiological mechanisms are not understood. In order to study the role of mtFASII in the regulation of energy metabolism we performed a comprehensive metabolic phenotyping with Seahorse technology proteomics in fibroblasts from healthy controls and ACSF3 patients. SILAC-based proteomics and lipidomic analysis were performed to investigate the effects of hypofunctional mtFASII on proteome and lipid homeostasis of complex lipids. Our data clearly confirmed an impaired mitochondrial flexibility characterized by reduced mitochondrial respiration and glycolytic flux due to a lower lipoylation degree. These findings were accompanied by the adaptational upregulation of β-oxidation and by the reduction of anaplerotic amino acids as compensatory mechanism to address the required energy need. Finally, lipidomic analysis demonstrated that the content of the bioactive lipids sphingomyelins and cardiolipins was strongly increased. Our data clearly demonstrate the role of mtFASII in metabolic regulation. Moreover, we show that mtFASII acts as mediator in the lipid-mediated signaling processes in the regulation of energy homeostasis and metabolic flexibility.

Keywords:  ACSF3; Energy metabolism; Metabolic flexibility; mtFASII

DOI:  https://doi.org/10.1016/j.bbalip.2019.07.012
Cell Metab. 2019 Aug 06. pii: S1550-4131(19)30380-8. [Epub ahead of print]30(2): 229-230

Acyl-CoA-Binding Protein Fuels Gliomagenesis.

Junfeng Bi, Paul S Mischel.

Altered lipid metabolism is common in glioblastoma, but its role in tumorigenesis is not well understood. In this issue of Cell Metabolism, Duman et al. (2019) provide new insight into this process, demonstrating that acyl-CoA-binding protein (ACBP) drives glioblastoma growth by promoting mitochondrial long fatty acyl-CoA accumulation and β-oxidation.

DOI: https://doi.org/10.1016/j.cmet.2019.07.007
Biochim Biophys Acta Mol Basis Dis. 2019 Jul 31. pii: S0925-4439(19)30240-6. [Epub ahead of print]

IDH2 deficiency impairs cutaneous wound healing via ROS-dependent apoptosis.

Sung Hwan Kim, Jeen-Woo Park.

  Dermal fibroblasts are mesenchymal cells found between the skin epidermis and subcutaneous tissue that play a pivotal role in cutaneous wound healing by synthesizing fibronectin (a component of the extracellular matrix), secreting angiogenesis factors, and generating strong contractile forces. In wound healing, low concentrations of reactive oxygen species (ROS) are essential in combating invading microorganisms and in cell-survival signaling. However, excessive ROS production impairs fibroblasts. Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) is a key enzyme that regulates the mitochondrial redox balance and reduces oxidative stress-induced cell injury through the generation of NADPH. In the present study, the downregulation of IDH2 expression resulted in an increase in cell apoptosis in mouse skin through ROS-dependent ATM-mediated p53 signaling. IDH2 deficiency also delayed cutaneous wound healing in mice and impaired dermal fibroblast function. Furthermore, pretreatment with the mitochondria-targeted antioxidant mito-TEMPO alleviated the apoptosis induced by IDH2 deficiency both in vitro and in vivo. Together, our findings highlight the role of IDH2 in cutaneous wound healing in association with mitochondrial ROS.

Keywords:  Apoptosis; IDH2; Mito-TEMPO; Mitochondria; Wound healing

DOI:  https://doi.org/10.1016/j.bbadis.2019.07.017
Int J Biochem Cell Biol. 2019 Aug 05. pii: S1357-2725(19)30157-8. [Epub ahead of print] 105580

Succinate in ischemia: where does it come from?

Christos Chinopoulos.

  During tissue ischemia succinate accumulates. Herein, literature spanning the past nine decades is reviewed leaning towards the far greater role of Krebs cycle's canonical activity yielding succinate through α-ketoglutarate -> succinyl-CoA -> succinate even in hypoxia, as opposed to reversal of succinate dehydrogenase. Furthermore, the concepts of i) a diode-like property of succinate dehydrogenase rendering it difficult to reverse, and ii) the absence of mammalian mitochondrial quinones exhibiting redox potentials in the [-60, -80] mV range needed for fumarate reduction, are discussed. Finally, it is emphasized that a "fumarate reductase" enzyme entity reducing fumarate to succinate found in some bacteria and lower eukaryotes remains to be discovered in mammalian mitochondria.

Keywords:  TCA cycle; anoxia; fumarate; hypoxia; substrate-level phosphorylation; succinate dehydrogenase

DOI:  https://doi.org/10.1016/j.biocel.2019.105580
EMBO Rep. 2019 Aug 06. e47425

Mitochondrial translocation of cyclin C stimulates intrinsic apoptosis through Bax recruitment.

Jan Jezek, Kai-Ti Chang, Amogh M Joshi, Randy Strich.

  Intrinsic apoptosis requires mitochondrial outer membrane disruption triggered by recruitment, activation, and oligomerization of the Bcl-2 homology protein Bax. Following oxidative stress, we demonstrated that the transcriptional regulator cyclin C is released into the cytosol where it directs mitochondrial fragmentation and efficient apoptotic induction. This study reveals that cytoplasmic cyclin C is required for both normal Bax activation and its efficient mitochondrial localization. This activity appears direct as cyclin C co-immunoprecipitates with active Bax in stressed cells and binds recombinant Bax in vitro. In addition, stable cyclin C-Bax association requires the fission complex. Pharmacologically stimulating cyclin C nuclear release is sufficient for Bax association and their mitochondrial localization in the absence of any stress signals. However, these cells do not undergo cell death as Bax fails to oligomerize. These data support a model that cyclin C association defines an initial step in Bax mitochondrial recruitment and provides a physical connection between the fission and apoptotic factors. This strategy allows the cell to discriminate stress-induced fission able to recruit Bax from other types of mitochondrial divisions.

Keywords:  Bcl-2 homology; Cdk8; apoptosis; cyclin C; mitochondria

DOI:  https://doi.org/10.15252/embr.201847425
Cancer Res. 2019 Aug 08. pii: canres.0708.2019. [Epub ahead of print]

CDK4 regulates lysosomal function and mTORC1 activation to promote cancer cell survival.

Laia Martínez-Carreres, Julien Puyal, Lucia C Leal-Esteban, Meritxell Orpinell, Judit Castillo-Armengol, Albert Giralt, Oleksandr Dergai, Catherine Moret, Valentin Barquissau, Anita Nasrallah, Angélique Pabois, Lianjun Zhang, Pedro Romero, Isabel Cristina Lopez-Mejia, Lluis Fajas.

Cyclin-dependent kinase 4 (CDK4) is well-known for its role in regulating the cell cycle, however, its role in cancer metabolism, especially mTOR signaling, is undefined. In this study, we established a connection between CDK4 and lysosomes, an emerging metabolic organelle crucial for mTORC1 activation. On the one hand, CDK4 phosphorylated the tumor suppressor FLCN, regulating mTORC1 recruitment to the lysosomal surface in response to amino acids. On the other hand, CDK4 directly regulated lysosomal function and was essential for lysosomal degradation, ultimately regulating mTORC1 activity. Pharmacological inhibition or genetic inactivation of CDK4, other than retaining FLCN at the lysosomal surface, led to the accumulation of undigested material inside lysosomes, which impaired the autophagic flux and induced cancer cell senescence in vitro and in xenograft models. Importantly, the use of CDK4 inhibitors in therapy is known to cause senescence but not cell death. To overcome this phenomenon and based on our findings, we increased the autophagic flux in cancer cells by using an AMPK activator in combination with a CDK4 inhibitor. The cotreatment induced autophagy (AMPK activation), and impaired lysosomal function (CDK4 inhibition), resulting in cell death and tumor regression. Altogether, we uncover a previously unknown role for CDK4 in lysosomal biology and propose a novel therapeutic strategy to target cancer cells.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-0708
Cell. 2019 Aug 08. pii: S0092-8674(19)30784-6. [Epub ahead of print]178(4): 933-948.e14

Opposing Functions of Interferon Coordinate Adaptive and Innate Immune Responses to Cancer Immune Checkpoint Blockade.

Joseph L Benci, Lexus R Johnson, Ruth Choa, Yuanming Xu, Jingya Qiu, Zilu Zhou, Bihui Xu, Darwin Ye, Katherine L Nathanson, Carl H June, E John Wherry, Nancy R Zhang, Hemant Ishwaran, Matthew D Hellmann, Jedd D Wolchok, Taku Kambayashi, Andy J Minn.

  Interferon-gamma (IFNG) augments immune function yet promotes T cell exhaustion through PDL1. How these opposing effects are integrated to impact immune checkpoint blockade (ICB) is unclear. We show that while inhibiting tumor IFNG signaling decreases interferon-stimulated genes (ISGs) in cancer cells, it increases ISGs in immune cells by enhancing IFNG produced by exhausted T cells (TEX). In tumors with favorable antigenicity, these TEX mediate rejection. In tumors with neoantigen or MHC-I loss, TEX instead utilize IFNG to drive maturation of innate immune cells, including a PD1+TRAIL+ ILC1 population. By disabling an inhibitory circuit impacting PD1 and TRAIL, blocking tumor IFNG signaling promotes innate immune killing. Thus, interferon signaling in cancer cells and immune cells oppose each other to establish a regulatory relationship that limits both adaptive and innate immune killing. In melanoma and lung cancer patients, perturbation of this relationship is associated with ICB response independent of tumor mutational burden.

Keywords:  CTLA4; ISGs; NK cells; PDL1; T cell exhaustion; immune checkpoint blockade; immunotherapy resistance; innate lymphoid cells; interferon

DOI:  https://doi.org/10.1016/j.cell.2019.07.019
Cell Metab. 2019 Jul 25. pii: S1550-4131(19)30377-8. [Epub ahead of print]

Fatty Acid Metabolites Combine with Reduced β Oxidation to Activate Th17 Inflammation in Human Type 2 Diabetes.

Dequina A Nicholas, Elizabeth A Proctor, Madhur Agrawal, Anna C Belkina, Stephen C Van Nostrand, Leena Panneerseelan-Bharath, Albert R Jones, Forum Raval, Blanche C Ip, Min Zhu, Jose M Cacicedo, Chloe Habib, Nestor Sainz-Rueda, Leah Persky, Patrick G Sullivan, Barbara E Corkey, Caroline M Apovian, Philip A Kern, Douglas A Lauffenburger, Barbara S Nikolajczyk.

  Mechanisms that regulate metabolites and downstream energy generation are key determinants of T cell cytokine production, but the processes underlying the Th17 profile that predicts the metabolic status of people with obesity are untested. Th17 function requires fatty acid uptake, and our new data show that blockade of CPT1A inhibits Th17-associated cytokine production by cells from people with type 2 diabetes (T2D). A low CACT:CPT1A ratio in immune cells from T2D subjects indicates altered mitochondrial function and coincides with the preference of these cells to generate ATP through glycolysis rather than fatty acid oxidation. However, glycolysis was not critical for Th17 cytokines. Instead, β oxidation blockade or CACT knockdown in T cells from lean subjects to mimic characteristics of T2D causes cells to utilize 16C-fatty acylcarnitine to support Th17 cytokines. These data show long-chain acylcarnitine combines with compromised β oxidation to promote disease-predictive inflammation in human T2D.

Keywords:  fatty acid oxidation; glycolysis; immunometabolism; metaflammation

DOI:  https://doi.org/10.1016/j.cmet.2019.07.004
J Mol Biol. 2019 Aug 02. pii: S0022-2836(19)30484-X. [Epub ahead of print]

Pyruvate Kinase Regulates the Pentose-Phosphate Pathway in Response to Hypoxia in Mycobacterium tuberculosis.

Wenhe Zhong, Jingjing Guo, Liang Cui, Yok Hian Chionh, Kuohan Li, Abbas El Sahili, Qixu Cai, Meng Yuan, Paul A M Michels, Linda A Fothergill-Gilmore, Malcolm D Walkinshaw, Yuguang Mu, Julien Lescar, Peter C Dedon.

  In response to the stress of infection, Mycobacterium tuberculosis (Mtb) reprograms its metabolism to accommodate nutrient and energetic demands in a changing environment. Pyruvate kinase (PYK) is an essential glycolytic enzyme in the phosphoenolpyruvate (PEP)-pyruvate-oxaloacetate node that is a central switch point for carbon flux distribution. Here we show that the competitive binding of pentose monophosphate inhibitors or the activator glucose 6-phosphate (G6P) to MtbPYK tightly regulates the metabolic flux. Intriguingly, pentose monophosphates were found to share the same binding site with G6P. The determination of a crystal structure of MtbPYK with bound ribose 5-phosphate (R5P), combined with biochemical analyses and molecular dynamic simulations, revealed that the allosteric inhibitor pentose monophosphate increases PYK structural dynamics, weakens the structural network communication, and impairs substrate binding. G6P on the other hand, primes and activates the tetramer by decreasing protein flexibility and strengthening allosteric coupling. Therefore, we propose that MtbPYK uses these differences in conformational dynamics to up- and down-regulate enzymatic activity. Importantly, metabolome profiling in mycobacteria reveals a significant increase in the levels of pentose monophosphate during hypoxia, which provides insights into how PYK uses dynamics of the tetramer as a competitive allosteric mechanism to retard glycolysis and facilitate metabolic reprogramming toward the pentose-phosphate pathway for achieving redox balance and an anticipatory metabolic response in Mtb.

Keywords:  Allosteric regulation; Metabolic reprogramming; Stress response; Structural dynamics

DOI:  https://doi.org/10.1016/j.jmb.2019.07.033
EMBO J. 2019 Aug 07. e101552

Hyperoxidation of mitochondrial peroxiredoxin limits H2 O2 -induced cell death in yeast.

Gaetano Calabrese, Esra Peker, Prince Saforo Amponsah, Michaela Nicole Hoehne, Trine Riemer, Marie Mai, Gerd Patrick Bienert, Marcel Deponte, Bruce Morgan, Jan Riemer.

  Hydrogen peroxide (H2 O2 ) plays important roles in cellular signaling, yet nonetheless is toxic at higher concentrations. Surprisingly, the mechanism(s) of cellular H2 O2 toxicity remain poorly understood. Here, we reveal an important role for mitochondrial 1-Cys peroxiredoxin from budding yeast, Prx1, in regulating H2 O2 -induced cell death. We show that Prx1 efficiently transfers oxidative equivalents from H2 O2 to the mitochondrial glutathione pool. Deletion of PRX1 abrogates glutathione oxidation and leads to a cytosolic adaptive response involving upregulation of the catalase, Ctt1. Both of these effects contribute to improved cell viability following an acute H2 O2 challenge. By replacing PRX1 with natural and engineered peroxiredoxin variants, we could predictably induce widely differing matrix glutathione responses to H2 O2 . Therefore, we demonstrated a key role for matrix glutathione oxidation in driving H2 O2 -induced cell death. Finally, we reveal that hyperoxidation of Prx1 serves as a switch-off mechanism to limit oxidation of matrix glutathione at high H2 O2 concentrations. This enables yeast cells to strike a fine balance between H2 O2 removal and limitation of matrix glutathione oxidation.

Keywords:  cell death; hydrogen peroxide; hyperoxidation; mitochondria; peroxiredoxin

DOI:  https://doi.org/10.15252/embj.2019101552
Nat Immunol. 2019 Aug 05.

Functional reprogramming of regulatory T cells in the absence of Foxp3.

Louis-Marie Charbonnier, Ye Cui, Emmanuel Stephen-Victor, Hani Harb, David Lopez, Jack J Bleesing, Maria I Garcia-Lloret, Karin Chen, Ahmet Ozen, Peter Carmeliet, Ming O Li, Matteo Pellegrini, Talal A Chatila.

Regulatory T cells (Treg cells) deficient in the transcription factor Foxp3 lack suppressor function and manifest an effector T (Teff) cell-like phenotype. We demonstrate that Foxp3 deficiency dysregulates metabolic checkpoint kinase mammalian target of rapamycin (mTOR) complex 2 (mTORC2) signaling and gives rise to augmented aerobic glycolysis and oxidative phosphorylation. Specific deletion of the mTORC2 adaptor gene Rictor in Foxp3-deficient Treg cells ameliorated disease in a Foxo1 transcription factor-dependent manner. Rictor deficiency re-established a subset of Treg cell genetic circuits and suppressed the Teff cell-like glycolytic and respiratory programs, which contributed to immune dysregulation. Treatment of Treg cells from patients with FOXP3 deficiency with mTOR inhibitors similarly antagonized their Teff cell-like program and restored suppressive function. Thus, regulatory function can be re-established in Foxp3-deficient Treg cells by targeting their metabolic pathways, providing opportunities to restore tolerance in Treg cell disorders.

DOI: https://doi.org/10.1038/s41590-019-0442-x
Cancer Metab. 2019 ;7 8

Inhibition of phosphoenolpyruvate carboxykinase blocks lactate utilization and impairs tumor growth in colorectal cancer.

Emily D Montal, Kavita Bhalla, Ruby E Dewi, Christian F Ruiz, John A Haley, Ashley E Ropell, Chris Gordon, John D Haley, Geoffrey D Girnun.

  Background: Metabolic reprogramming is a key feature of malignant cells. While glucose is one of the primary substrates for malignant cells, cancer cells also display a remarkable metabolic flexibility. Depending on nutrient availability and requirements, cancer cells will utilize alternative fuel sources to maintain the TCA cycle for bioenergetic and biosynthetic requirements. Lactate was typically viewed as a passive byproduct of cancer cells. However, studies now show that lactate is an important substrate for the TCA cycle in breast, lung, and pancreatic cancer.Methods: Metabolic analysis of colorectal cancer (CRC) cells was performed using a combination of bioenergetic analysis and 13C stable isotope tracing.
Results: We show here that CRC cells use lactate to fuel the TCA cycle and promote growth especially under nutrient-deprived conditions. This was mediated in part by maintaining cellular bioenergetics. Therefore targeting the ability of cancer cells to utilize lactate via the TCA cycle would have a significant therapeutic benefit. Phosphoenolpyruvate carboxykinase (PEPCK) is an important cataplerotic enzyme that promotes TCA cycle activity in CRC cells. Treatment of CRC cells with low micromolar doses of a PEPCK inhibitor (PEPCKi) developed for diabetes decreased cell proliferation and utilization of lactate by the TCA cycle in vitro and in vivo. Mechanistically, we observed that the PEPCKi increased nutrient stress as determined by decreased cellular bioenergetics including decreased respiration, ATP levels, and increased AMPK activation. 13C stable isotope tracing showed that the PEPCKi decreased the incorporation of lactate into the TCA cycle.
Conclusions: These studies highlight lactate as an important substrate for CRC and the use of PEPCKi as a therapeutic approach to target lactate utilization in CRC cells.

Keywords:  Cancer metabolism; Lactate; Metabolic flexibility; PEPCK; TCA cycle

DOI:  https://doi.org/10.1186/s40170-019-0199-6
Dev Cell. 2019 Aug 05. pii: S1534-5807(19)30626-4. [Epub ahead of print]50(3): 261-263

EGFR Pathway Links Amino Acid Levels and Induction of Macropinocytosis.

Vajira K Weerasekara, Krushna C Patra, Nabeel Bardeesy.

Macropinocytosis coordinates non-specific uptake of macromolecules and fluid. Cancers employ macropinocytosis to obtain nutrients to support their metabolic homeostasis. In this issue of Developmental Cell, Lee et al. (2019) report that glutamine deprivation boosts macropinocytosis via EGFR signaling induction, providing a fine-tuned mechanism by which cancers adapt to nutrient supply.

DOI: https://doi.org/10.1016/j.devcel.2019.07.020
Front Physiol. 2019 ;10 733

Mitofusin 2 Is Essential for IP3-Mediated SR/Mitochondria Metabolic Feedback in Ventricular Myocytes.

Lea K Seidlmayer, Christine Mages, Annette Berbner, Petra Eder-Negrin, Paula Anahi Arias-Loza, Mathias Kaspar, Moshi Song, Gerald W Dorn Ii, Michael Kohlhaas, Stefan Frantz, Christoph Maack, Brenda Gerull, Elena N Dedkova.

  Aim: Endothelin-1 (ET-1) and angiotensin II (Ang II) are multifunctional peptide hormones that regulate the function of the cardiovascular and renal systems. Both hormones increase the intracellular production of inositol-1,4,5-trisphosphate (IP3) by activating their membrane-bound receptors. We have previously demonstrated that IP3-mediated sarcoplasmic reticulum (SR) Ca2+ release results in mitochondrial Ca2+ uptake and activation of ATP production. In this study, we tested the hypothesis that intact SR/mitochondria microdomains are required for metabolic IP3-mediated SR/mitochondrial feedback in ventricular myocytes. Methods: As a model for disrupted mitochondrial/SR microdomains, cardio-specific tamoxifen-inducible mitofusin 2 (Mfn2) knock out (KO) mice were used. Mitochondrial Ca2+ uptake, membrane potential, redox state, and ATP generation were monitored in freshly isolated ventricular myocytes from Mfn2 KO mice and their control wild-type (WT) littermates. Results: Stimulation of ET-1 receptors in healthy control myocytes increases mitochondrial Ca2+ uptake, maintains mitochondrial membrane potential and redox balance leading to the enhanced ATP generation. Mitochondrial Ca2+ uptake upon ET-1 stimulation was significantly higher in interfibrillar (IFM) and perinuclear (PNM) mitochondria compared to subsarcolemmal mitochondria (SSM) in WT myocytes. Mfn2 KO completely abolished mitochondrial Ca2+ uptake in IFM and PNM mitochondria but not in SSM. However, mitochondrial Ca2+ uptake induced by beta-adrenergic receptors activation with isoproterenol (ISO) was highest in SSM, intermediate in IFM, and smallest in PNM regions. Furthermore, Mfn2 KO did not affect ISO-induced mitochondrial Ca2+ uptake in SSM and IFM mitochondria; however, enhanced mitochondrial Ca2+ uptake in PNM. In contrast to ET-1, ISO induced a decrease in ATP levels in WT myocytes. Mfn2 KO abolished ATP generation upon ET-1 stimulation but increased ATP levels upon ISO application with highest levels observed in PNM regions. Conclusion: When the physical link between SR and mitochondria by Mfn2 was disrupted, the SR/mitochondrial metabolic feedback mechanism was impaired resulting in the inability of the IP3-mediated SR Ca2+ release to induce ATP production in ventricular myocytes from Mfn2 KO mice. Furthermore, we revealed the difference in Mfn2-mediated SR-mitochondrial communication depending on mitochondrial location and type of communication (IP3R-mRyR1 vs. ryanodine receptor type 2-mitochondrial calcium uniporter).

Keywords:  ATP generation; IP3 signaling; Mfn2 KO mice; SR/mitochondria metabolic feedback; endothelin-1; mitochondrial mRyR1; mitofusin 2

DOI:  https://doi.org/10.3389/fphys.2019.00733
Biochim Biophys Acta Bioenerg. 2019 Aug 05. pii: S0005-2728(19)30100-8. [Epub ahead of print] 148061

Functional analysis of coiled-coil domains of MCU in mitochondrial calcium uptake.

Takenori Yamamoto, Mizune Ozono, Akira Watanabe, Kosuke Maeda, Atsushi Nara, Mei Hashida, Yusuke Ido, Yuka Hiroshima, Akiko Yamada, Hiroshi Terada, Yasuo Shinohara.

  The mitochondrial calcium uniporter (MCU) complex is a highly-selective calcium channel. This complex consists of MCU, mitochondrial calcium uptake proteins (MICUs), MCU regulator 1 (MCUR1), essential MCU regulator element (EMRE), etc. MCU, which is the pore-forming subunit, has 2 highly conserved coiled-coil domains (CC1 and CC2); however, their functional roles are unknown. The yeast expression system of mammalian MCU and EMRE enables precise reconstitution of the properties of the mammalian MCU complex in yeast mitochondria. Using the yeast expression system, we here showed that, when MCU mutant lacking CC1 or CC2 was expressed together with EMRE in yeast, their mitochondrial Ca2+-uptake function was lost. Additionally, point mutations in CC1 or CC2, which were expected to prevent the formation of the coiled coil, also disrupted the Ca2+-uptake function. Thus, it is essential for the Ca2+ uptake function of MCU that the coiled-coil structure be formed in CC1 and CC2. The loss of function of those mutated MCUs was also observed in the mitochondria of a yeast strain lacking the yeast MCUR1 homolog. Also, in the D. discoideum MCU, which has EMRE-independent Ca2+-uptake function, the deletion of either CC1 or CC2 caused the loss of function. These results indicated that the critical functions of CC1 and CC2 were independent of other regulatory subunits such as MCUR1 and EMRE, suggesting that CC1 and CC2 might be essential for pore formation by MCUs themselves. Based on the tetrameric structure of MCU, we discussed the functional roles of the coiled-coil domains of MCU.

Keywords:  Calcium uniporter; Coiled coil; Ion channel; MCU; Mitochondria; Yeast

DOI:  https://doi.org/10.1016/j.bbabio.2019.148061
Cell Rep. 2019 Aug 06. pii: S2211-1247(19)30923-4. [Epub ahead of print]28(6): 1538-1550.e7

Isoform-Specific Destabilization of the Active Site Reveals a Molecular Mechanism of Intrinsic Activation of KRas G13D.

Christian W Johnson, Yi-Jang Lin, Derion Reid, Jillian Parker, Spiro Pavlopoulos, Patrick Dischinger, Carrie Graveel, Andrew J Aguirre, Matthew Steensma, Kevin M Haigis, Carla Mattos.

  Ras GTPases are mutated at codons 12, 13, and 61, with different frequencies in KRas, HRas, and NRas and in a cancer-specific manner. The G13D mutant appears in 25% of KRas-driven colorectal cancers, while observed only rarely in HRas or NRas. Structures of Ras G13D in the three isoforms show an open active site, with adjustments to the D13 backbone torsion angles and with disconnected switch regions. KRas G13D has unique features that destabilize the nucleotide-binding pocket. In KRas G13D bound to GDP, A59 is placed in the Mg2+ binding site, as in the HRas-SOS complex. Structure and biochemistry are consistent with an intermediate level of KRas G13D bound to GTP, relative to wild-type and KRas G12D, observed in genetically engineered mouse models. The results explain in part the elevated frequency of the G13D mutant in KRas over the other isoforms of Ras.

Keywords:  KRas G12D; KRas G13D mouse model; KRas G13D structures; Ras GTPases; Ras conformational states; activation cycle; colorectal cancer; nucleotide exchange mutant; oncogene

DOI:  https://doi.org/10.1016/j.celrep.2019.07.026
Nature. 2019 Aug 07.

BORIS promotes chromatin regulatory interactions in treatment-resistant cancer cells.

David N Debruyne, Ruben Dries, Satyaki Sengupta, Davide Seruggia, Yang Gao, Bandana Sharma, Hao Huang, Lisa Moreau, Michael McLane, Daniel S Day, Eugenio Marco, Ting Chen, Nathanael S Gray, Kwok-Kin Wong, Stuart H Orkin, Guo-Cheng Yuan, Richard A Young, Rani E George.

The CCCTC-binding factor (CTCF), which anchors DNA loops that organize the genome into structural domains, has a central role in gene control by facilitating or constraining interactions between genes and their regulatory elements1,2. In cancer cells, the disruption of CTCF binding at specific loci by somatic mutation3,4 or DNA hypermethylation5 results in the loss of loop anchors and consequent activation of oncogenes. By contrast, the germ-cell-specific paralogue of CTCF, BORIS (brother of the regulator of imprinted sites, also known as CTCFL)6, is overexpressed in several cancers7-9, but its contributions to the malignant phenotype remain unclear. Here we show that aberrant upregulation of BORIS promotes chromatin interactions in ALK-mutated, MYCN-amplified neuroblastoma10 cells that develop resistance to ALK inhibition. These cells are reprogrammed to a distinct phenotypic state during the acquisition of resistance, a process defined by the initial loss of MYCN expression followed by subsequent overexpression of BORIS and a concomitant switch in cellular dependence from MYCN to BORIS. The resultant BORIS-regulated alterations in chromatin looping lead to the formation of super-enhancers that drive the ectopic expression of a subset of proneural transcription factors that ultimately define the resistance phenotype. These results identify a previously unrecognized role of BORIS-to promote regulatory chromatin interactions that support specific cancer phenotypes.

DOI: https://doi.org/10.1038/s41586-019-1472-0
Cell Metab. 2019 Aug 06. pii: S1550-4131(19)30382-1. [Epub ahead of print]30(2): 231-232

Mitochondrial DNA Inheritance in Humans: Mix, Match, and Survival of the Fittest.

Anu Suomalainen.

Mitochondrial DNA (mtDNA) sequence variation and maternal inheritance are valuable tools in assessing ancestry of different human populations and for clinical practice. A new study (Wei et al., 2019) reports that the fate of new mtDNA variants in the female germline is non-random as they report functional selection and matching to nuclear ancestry to shape human mtDNA variation.

DOI: https://doi.org/10.1016/j.cmet.2019.07.009
Nat Immunol. 2019 Aug 05.

Rerouting metabolism to activate macrophages.

Michael P Murphy.

DOI: https://doi.org/10.1038/s41590-019-0455-5
Mol Cell. 2019 Jul 19. pii: S1097-2765(19)30488-5. [Epub ahead of print]

MISTERMINATE Mechanistically Links Mitochondrial Dysfunction with Proteostasis Failure.

Zhihao Wu, Ishaq Tantray, Junghyun Lim, Songjie Chen, Yu Li, Zoe Davis, Cole Sitron, Jason Dong, Suzana Gispert, Georg Auburger, Onn Brandman, Xiaolin Bi, Michael Snyder, Bingwei Lu.

  Mitochondrial dysfunction and proteostasis failure frequently coexist as hallmarks of neurodegenerative disease. How these pathologies are related is not well understood. Here, we describe a phenomenon termed MISTERMINATE (mitochondrial-stress-induced translational termination impairment and protein carboxyl terminal extension), which mechanistically links mitochondrial dysfunction with proteostasis failure. We show that mitochondrial dysfunction impairs translational termination of nuclear-encoded mitochondrial mRNAs, including complex-I 30kD subunit (C-I30) mRNA, occurring on the mitochondrial surface in Drosophila and mammalian cells. Ribosomes stalled at the normal stop codon continue to add to the C terminus of C-I30 certain amino acids non-coded by mRNA template. C-terminally extended C-I30 is toxic when assembled into C-I and forms aggregates in the cytosol. Enhancing co-translational quality control prevents C-I30 C-terminal extension and rescues mitochondrial and neuromuscular degeneration in a Parkinson's disease model. These findings emphasize the importance of efficient translation termination and reveal unexpected link between mitochondrial health and proteome homeostasis mediated by MISTERMINATE.

Keywords:  CAT-tailing; MISTERMINATE; PINK1/Parkin; Parkinson’s disease; RQC; mitochondrial stress; neurodegeneration; proteostasis; ribosome stalling; translation termination

DOI:  https://doi.org/10.1016/j.molcel.2019.06.031
Cell. 2019 Aug 08. pii: S0092-8674(19)30830-X. [Epub ahead of print]178(4): 807-819.e21

The Oncogenic Action of NRF2 Depends on De-glycation by Fructosamine-3-Kinase.

Viraj R Sanghvi, Josef Leibold, Marco Mina, Prathibha Mohan, Marjan Berishaj, Zhuoning Li, Matthew M Miele, Nathalie Lailler, Chunying Zhao, Elisa de Stanchina, Agnes Viale, Leila Akkari, Scott W Lowe, Giovanni Ciriello, Ronald C Hendrickson, Hans-Guido Wendel.

  The NRF2 transcription factor controls a cell stress program that is implicated in cancer and there is great interest in targeting NRF2 for therapy. We show that NRF2 activity depends on Fructosamine-3-kinase (FN3K)-a kinase that triggers protein de-glycation. In its absence, NRF2 is extensively glycated, unstable, and defective at binding to small MAF proteins and transcriptional activation. Moreover, the development of hepatocellular carcinoma triggered by MYC and Keap1 inactivation depends on FN3K in vivo. N-acetyl cysteine treatment partially rescues the effects of FN3K loss on NRF2 driven tumor phenotypes indicating a key role for NRF2-mediated redox balance. Mass spectrometry reveals that other proteins undergo FN3K-sensitive glycation, including translation factors, heat shock proteins, and histones. How glycation affects their functions remains to be defined. In summary, our study reveals a surprising role for the glycation of cellular proteins and implicates FN3K as targetable modulator of NRF2 activity in cancer.

Keywords:  EGFR; FN3K; KEAP1; NRF2; de-glycation; fructosamine; glucose; glycation; hepatocellular carcinoma; redox

DOI:  https://doi.org/10.1016/j.cell.2019.07.031
Cell. 2019 Aug 08. pii: S0092-8674(19)30796-2. [Epub ahead of print]178(4): 901-918.e16

Sex Differences in Intestinal Carbohydrate Metabolism Promote Food Intake and Sperm Maturation.

Bruno Hudry, Eva de Goeij, Alessandro Mineo, Pedro Gaspar, Dafni Hadjieconomou, Chris Studd, Joao B Mokochinski, Holger B Kramer, Pierre-Yves Plaçais, Thomas Preat, Irene Miguel-Aliaga.

  Physiology and metabolism are often sexually dimorphic, but the underlying mechanisms remain incompletely understood. Here, we use the intestine of Drosophila melanogaster to investigate how gut-derived signals contribute to sex differences in whole-body physiology. We find that carbohydrate handling is male-biased in a specific portion of the intestine. In contrast to known sexual dimorphisms in invertebrates, the sex differences in intestinal carbohydrate metabolism are extrinsically controlled by the adjacent male gonad, which activates JAK-STAT signaling in enterocytes within this intestinal portion. Sex reversal experiments establish roles for this male-biased intestinal metabolic state in controlling food intake and sperm production through gut-derived citrate. Our work uncovers a male gonad-gut axis coupling diet and sperm production, revealing that metabolic communication across organs is physiologically important. The instructive role of citrate in inter-organ communication might be significant in more biological contexts than previously recognized.

Keywords:  Drosophila; carbohydrate metabolism; citrate; gender differences; gonad; intestine; organ plasticity; sexual dimorphisms; sperm; testes

DOI:  https://doi.org/10.1016/j.cell.2019.07.029
Front Oncol. 2019 ;9 640

European mtDNA Variants Are Associated With Differential Responses to Cisplatin, an Anticancer Drug: Implications for Drug Resistance and Side Effects.

Tej H Patel, Lucas Norman, Steven Chang, Sina Abedi, Catherine Liu, Marilyn Chwa, Shari R Atilano, Kunal Thaker, Stephanie Lu, S Michal Jazwinski, Michael V Miceli, Nitin Udar, Daniela Bota, M Cristina Kenney.

  Background: Cisplatin, a powerful antitumor agent, causes formation of DNA adducts, and activation of apoptotic pathways. Presently, cisplatin resistance develops in up to 70% of patients but the underlying molecular mechanism(s) are unclear and there are no markers to determine which patients will become resistant. Mitochondria play a significant role not only in energy metabolism but also retrograde signaling (mitochondria to nucleus) that modulates inflammation, complement, and apoptosis pathways. Maternally inherited mitochondrial (mt) DNA can be classified into haplogroups representing different ethnic populations that have diverse susceptibilities to diseases and medications. Methods: Transmitochondrial cybrids, where all cell lines possess identical nuclear genomes but either the H (Southern European) or J (Northern European) mtDNA haplogroups, were treated with cisplatin and analyzed for differential responses related to viability, oxidative stress, and expression levels of genes associated with cancer, cisplatin-induced nephrotoxicity and resistance, apoptosis and signaling pathways. Results: The cisplatin-treated-J cybrids showed greater loss of cell viability along with lower levels of reactive oxygen species and mitochondrial membrane potential compared to cisplatin-treated-H cybrids. After cisplatin treatment, J cybrids showed increased gene expression of BAX, CASP3, and CYP51A, but lower levels of SFRP1 compared to untreated-J cybrids. The cisplatin-treated-H cybrids had elevated expression of CDKN1A/P21, which has a role in cisplatin toxicity, compared to untreated-H cybrids. The cisplatin-treated H had higher transcription levels of ABCC1, DHRS2/HEP27, and EFEMP1 compared to cisplatin-treated-J cybrids. Conclusions: Cybrid cell lines that contain identical nuclei but either H mtDNA mitochondria or J mtDNA mitochondria respond differently to cisplatin treatments suggesting involvement of the retrograde signaling (from mitochondria to nucleus) in the drug-induced cell death. Varying toxicities and transcription levels of the H vs. J cybrids after cisplatin treatment support the hypothesis that mtDNA variants play a role in the expression of genes affecting resistance and side effects of cisplatin.

Keywords:  cisplatin; cybrids; drug resistance; mitochondria; mtDNA haplogroups

DOI:  https://doi.org/10.3389/fonc.2019.00640
JCI Insight. 2019 Aug 08. pii: 129556. [Epub ahead of print]5

Dual peroxisome-proliferator-activated-receptor-α/γ activation inhibits SIRT1-PGC1α axis and causes cardiac dysfunction.

Charikleia Kalliora, Ioannis D Kyriazis, Shin-Ichi Oka, Melissa J Lieu, Yujia Yue, Estela Area-Gomez, Christine J Pol, Ying Tian, Wataru Mizushima, Adave Chin, Diego Scerbo, P Christian Schulze, Mete Civelek, Junichi Sadoshima, Muniswamy Madesh, Ira J Goldberg, Konstantinos Drosatos.

  Dual peroxisome proliferator-activated receptor (PPAR)α/γ agonists that were developed to target hyperlipidemia and hyperglycemia in type 2 diabetes patients, caused cardiac dysfunction or other adverse effects. We studied the mechanisms that underlie the cardiotoxic effects of a dual PPARα/γ agonist, tesaglitazar, in wild type and diabetic (leptin receptor deficient - db/db) mice. Mice treated with tesaglitazar-containing chow or high fat diet developed cardiac dysfunction despite lower plasma triglycerides and glucose levels. Expression of cardiac peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which promotes mitochondrial biogenesis, had the most profound reduction among various fatty acid metabolism genes. Furthermore, we observed increased acetylation of PGC1α, which suggests PGC1α inhibition and lowered sirtuin 1 (SIRT1) expression. This change was associated with lower mitochondrial abundance. Combined pharmacological activation of PPARα and PPARγ in C57BL/6 mice reproduced the reduction of PGC1α expression and mitochondrial abundance. Resveratrol-mediated SIRT1 activation attenuated tesaglitazar-induced cardiac dysfunction and corrected myocardial mitochondrial respiration in C57BL/6 and diabetic mice but not in cardiomyocyte-specific Sirt1-/- mice. Our data shows that drugs, which activate both PPARα and PPARγ lead to cardiac dysfunction associated with PGC1α suppression and lower mitochondrial abundance likely due to competition between these two transcription factors.

Keywords:  Diabetes; Heart failure; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/jci.insight.129556
Int J Cancer. 2019 Aug 09.

Oxidative phosphorylation as a potential therapeutic target for cancer therapy.

Valentina Sica, José Manuel Bravo-San Pedro, Gautier Stoll, Guido Kroemer.

  In contrast to prior belief, cancer cells require oxidative phosphorylation (OXPHOS) to strive, and exacerbated OXPHOS dependency frequently characterizes cancer stem cells, as well as primary or acquired resistance against chemotherapy or tyrosine kinase inhibitors. A growing arsenal of therapeutic agents is being designed to suppress the transfer of mitochondria from stromal to malignant cells, to interfere with mitochondrial biogenesis, to directly inhibit respiratory chain complexes, or to disrupt mitochondrial function in other ways. For the experimental treatment of cancers, OXPHOS inhibitors can be advantageously combined with tyrosine kinase inhibitors, as well as with other strategies to inhibit glycolysis, thereby causing a lethal energy crisis. Unfortunately, most of the preclinical data arguing in favor of OXPHOS inhibition have been obtained in xenograft models, in which human cancer cells are implanted in immunodeficient mice. Future studies on OXPHOS inhibitors should elaborate optimal treatment schedules and combination regimens that stimulate - or at least are compatible with - anticancer immune responses for long-term tumor control. This article is protected by copyright. All rights reserved.

Keywords:  Warburg phenomenon; bioenergetics; immunotherapy; metabolism; mitochondrial respiration

DOI:  https://doi.org/10.1002/ijc.32616
Cancer Res. 2019 Aug 07. pii: canres.0054.2019. [Epub ahead of print]

Mutant IDH sensitizes gliomas to endoplasmic reticulum stress and triggers apoptosis by MicroRNA183-mediated inhibition of Semaphorin 3E.

Ying Zhang, Stefan Pusch, James Innes, Kastytis Sidlauskas, Matthew Ellis, Joanne Lau, Tedani El-Hassan, Natasha Aley, Francesca Launchbury, Angela Richard-Loendt, Jasper de Boer, Sheng Chen, Lei Wang, Andreas von Deimling, Ningning Li, Sebastian Brandner.

Human astrocytomas and oligodendrogliomas are defined by mutations of the metabolic enzymes isocitrate dehydrogenase (IDH) 1 or 2, resulting in the production of the abnormal metabolite D-2 hydroxyglutarate. Here, we studied the effect of mutant IDH on cell proliferation and apoptosis in a glioma mouse model. Tumors were generated by inactivating Pten and p53 in forebrain progenitors and compared with tumors additionally expressing the Idh1 R132H mutation. Idh-mutant cells proliferated less in vitro and mice with Idh-mutant tumors survived significantly longer compared to Idh-wildtype mice. Comparison of micro-RNA and RNA expression profiles of Idh-wildtype and Idh-mutant cells and tumors revealed miR183 was significantly upregulated in IDH-mutant cells. Idh-mutant cells were more sensitive to endoplasmic reticulum (ER) stress, resulting in increased apoptosis and thus reduced cell proliferation and survival. This was mediated by the interaction of miR183 with the 5' untranslated region of Semaphorin3E, downregulating its function as an apoptosis suppressor. In conclusion, we show that mutant Idh1 delays tumorigenesis, and sensitizes tumor cells to ER stress and apoptosis. This may open opportunities for drug treatments targeting the miR183-semaphorin axis.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-0054
EMBO Rep. 2019 Aug 05. e48115

Lin28 enhances de novo fatty acid synthesis to promote cancer progression via SREBP-1.

Yang Zhang, Chenchen Li, Chuanzhen Hu, Qian Wu, Yongping Cai, Songge Xing, Hui Lu, Lin Wang, De Huang, Linchong Sun, Tingting Li, Xiaoping He, Xiuying Zhong, Junfeng Wang, Ping Gao, Zachary J Smith, Weidong Jia, Huafeng Zhang.

  Lin28 plays an important role in promoting tumor development, whereas its exact functions and underlying mechanisms are largely unknown. Here, we show that both human homologs of Lin28 accelerate de novo fatty acid synthesis and promote the conversion from saturated to unsaturated fatty acids via the regulation of SREBP-1. By directly binding to the mRNAs of both SREBP-1 and SCAP, Lin28A/B enhance the translation and maturation of SREBP-1, and protect cancer cells from lipotoxicity. Lin28A/B-stimulated tumor growth is abrogated by SREBP-1 inhibition and by the impairment of the RNA binding properties of Lin28A/B, respectively. Collectively, our findings uncover that post-transcriptional regulation by Lin28A/B enhances de novo fatty acid synthesis and metabolic conversion of saturated and unsaturated fatty acids via SREBP-1, which is critical for cancer progression.

Keywords:  Lin28; SREBP cleavage-activating protein; SREBP-1; de novo fatty acid synthesis; lipotoxicity; saturated and unsaturated fatty acids

DOI:  https://doi.org/10.15252/embr.201948115
Dev Cell. 2019 Aug 05. pii: S1534-5807(19)30625-2. [Epub ahead of print]50(3): 259-260

Knowing When to Let Go: Lysosomes Regulate Inter-Mitochondrial Tethering.

Alyssa M English, Adam L Hughes.

In this issue of Developmental Cell, Wong et al. (2019) show that the lysosomal GTPase Rab7 regulates inter-mitochondrial contacts to control mitochondrial motility and identify dysregulated inter-mitochondrial tethering as a common theme in Charcot-Marie-Tooth (CMT) type 2 disease.

DOI: https://doi.org/10.1016/j.devcel.2019.07.019
Aging (Albany NY). 2019 Aug 04.

Glucose dysregulation in pre-clinical Alzheimer's disease.

Niamh M C Connolly, Pierre Theurey, Paola Pizzo.



Keywords:  Alzheimer’s disease; bioenergetics; glucose metabolism; mitochondria; systems biology

DOI:  https://doi.org/10.18632/aging.102146
Cell Signal. 2019 Aug 05. pii: S0898-6568(19)30180-9. [Epub ahead of print] 109384

O-GlcNAcylated c-Jun antagonizes ferroptosis via inhibiting GSH synthesis in liver cancer.

Yan Chen, Guoqing Zhu, Ya Liu, Qi Wu, Xiao Zhang, Zhixuan Bian, Yue Zhang, Qiuhui Pan, Fenyong Sun.

  Ferroptosis is a metabolism-related cell death. Stimulating ferroptosis in liver cancer cells is a strategy to treat liver cancer. However, how to eradicate liver cancer cells through ferroptosis and the obstacles to inducing ferroptosis in liver cancer remain unclear. Here, we observed that erastin suppressed the malignant phenotypes of liver cancer cells by inhibiting O-GlcNAcylation of c-Jun and further inhibited protein expression, transcription activity and nuclear accumulation of c-Jun. Overexpression of c-Jun-WT with simultaneous PuGNAc treatment conversely inhibited erastin-induced ferroptosis, whereas overexpression of c-Jun-WT alone or overexpression of c-Jun-S73A (a non-O-GlcNAcylated form of c-Jun) with PuGNAc treatment did not exert a similar effect. GSH downregulation induced by erastin was restored by overexpression of c-Jun-WT with simultaneous PuGNAc treatment. In addition, overexpression of c-Jun-WT, but not its S73A mutant, induced PSAT1 and CBS transcription via directly binding to their promoter regions, suggesting that GSH synthesis is regulated by O-GlcNAcylated c-Jun. A positive correlation between c-Jun O-GlcNAcylation and GSH was observed in clinical samples. Collectively, O-GlcNAcylated c-Jun represents an obstructive factor to ferroptosis, and targeting O-GlcNAcylated c-Jun might be helpful for treating liver cancer.

Keywords:  Erastin; Glutathione; O-GlcNAcylation; Phosphorylation; Promoter; Transcription

DOI:  https://doi.org/10.1016/j.cellsig.2019.109384
Nature. 2019 Aug;572(7768): 157

Matching tumours to treatment buys time for those with a deadly cancer.



Keywords:  Cancer

DOI:  https://doi.org/10.1038/d41586-019-02349-2