bims-camemi 2020-10-18 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2020–10–18
27 papers selected by
Christian Frezza, , University of Cambridge, MRC Cancer Unit

Nuclear metabolism and the regulation of the epigenome.
Age-induced mitochondrial DNA point mutations are inadequate to alter metabolic homeostasis in response to nutrient challenge.
Structure of inhibitor-bound mammalian complex I.
Impaired flickering of the permeability transition pore causes SPG7 spastic paraplegia.
Neuronal AMPK coordinates mitochondrial energy sensing and hypoxia resistance in C. elegans.
Oxygen Glucose Deprivation Induced Prosurvival Autophagy Is Insufficient to Rescue Endothelial Function.
MICOS subcomplexes assemble independently on the mitochondrial inner membrane in proximity to ER contact sites.
The Ccr4-Not complex regulates TORC1 signaling and mitochondrial metabolism by promoting vacuole V-ATPase activity.
Chronic cold exposure enhances glucose oxidation in brown adipose tissue.
Mammalian lipid droplets are innate immune hubs integrating cell metabolism and host defense.
Functional interplay among thiol-based redox signaling, metabolism, and ferroptosis unveiled by a genetic variant of TP53.
Regulation of nutrient uptake by AMP-activated protein kinase.
Collective cancer cell invasion requires RNA accumulation at the invasive front.
Emerging roles for non-selenium containing ER-resident glutathione peroxidases in cell signaling and disease.
Visualizing, quantifying and manipulating mitochondrial DNA in vivo.
Role of the Mitochondrial Pyruvate Carrier in the Occurrence of Metabolic Inflexibility in Drosophila melanogaster Exposed to Dietary Sucrose.
Regulatory t cell metabolism at the intersection between autoimmune diseases and cancer.
Cancer Plasticity: The Role of mRNA Translation.
Inhibition of the mitochondrial ATPase function by IF1 changes the spatiotemporal organization of ATP synthase.
cGAS suppresses genomic instability as a decelerator of replication forks.
Comprehensive quantification of fuel use by the failing and nonfailing human heart.
Mind your media.
Regulation of Thiamine (Vitamin B1)-Dependent Metabolism in Mammals by p53.
Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation.
The role of stress kinases in metabolic disease.
The GATOR-Rag GTPase pathway inhibits mTORC1 activation by lysosome-derived amino acids.
Targeting KRAS(G12C): From Inhibitory Mechanism to Modulation of Antitumor Effects in Patients.

Nat Metab. 2020 Oct 12.

Nuclear metabolism and the regulation of the epigenome.

Ruben Boon, Giorgia G Silveira, Raul Mostoslavsky.

Cellular metabolism has emerged as a major biological node governing cellular behaviour. Metabolic pathways fuel cellular energy needs, providing basic chemical molecules to sustain cellular homeostasis, proliferation and function. Changes in nutrient consumption or availability therefore can result in complete reprogramming of cellular metabolism towards stabilizing core metabolite pools, such as ATP, S-adenosyl methionine, acetyl-CoA, NAD/NADP and α-ketoglutarate. Because these metabolites underlie a variety of essential metabolic reactions, metabolism has evolved to operate in separate subcellular compartments through diversification of metabolic enzyme complexes, oscillating metabolic activity and physical separation of metabolite pools. Given that these same core metabolites are also consumed by chromatin modifiers in the establishment of epigenetic signatures, metabolite consumption on and release from chromatin directly influence cellular metabolism and gene expression. In this Review, we highlight recent studies describing the mechanisms determining nuclear metabolism and governing the redistribution of metabolites between the nuclear and non-nuclear compartments.

DOI: https://doi.org/10.1038/s42255-020-00285-4
Aging Cell. 2020 Oct 13. e13166

Age-induced mitochondrial DNA point mutations are inadequate to alter metabolic homeostasis in response to nutrient challenge.

Timothy M Moore, Zhenqi Zhou, Alexander R Strumwasser, Whitaker Cohn, Amanda J Lin, Kevin Cory, Kate Whitney, Theodore Ho, Timothy Ho, Joseph L Lee, Daniel H Rucker, Austin N Hoang, Kevin Widjaja, Aaron D Abrishami, Sarada Charugundla, Linsey Stiles, Julian P Whitelegge, Lorraine P Turcotte, Jonathan Wanagat, Andrea L Hevener.

  Mitochondrial dysfunction is frequently associated with impairment in metabolic homeostasis and insulin action, and is thought to underlie cellular aging. However, it is unclear whether mitochondrial dysfunction is a cause or consequence of insulin resistance in humans. To determine the impact of intrinsic mitochondrial dysfunction on metabolism and insulin action, we performed comprehensive metabolic phenotyping of the polymerase gamma (PolG) D257A "mutator" mouse, a model known to accumulate supraphysiological mitochondrial DNA (mtDNA) point mutations. We utilized the heterozygous PolG mutator mouse (PolG+/mut ) because it accumulates mtDNA point mutations ~ 500-fold > wild-type mice (WT), but fails to develop an overt progeria phenotype, unlike PolGmut/mut animals. To determine whether mtDNA point mutations induce metabolic dysfunction, we examined male PolG+/mut mice at 6 and 12 months of age during normal chow feeding, after 24-hr starvation, and following high-fat diet (HFD) feeding. No marked differences were observed in glucose homeostasis, adiposity, protein/gene markers of metabolism, or oxygen consumption in muscle between WT and PolG+/mut mice during any of the conditions or ages studied. However, proteomic analyses performed on isolated mitochondria from 12-month-old PolG+/mut mouse muscle revealed alterations in the expression of mitochondrial ribosomal proteins, electron transport chain components, and oxidative stress-related factors compared with WT. These findings suggest that mtDNA point mutations at levels observed in mammalian aging are insufficient to disrupt metabolic homeostasis and insulin action in male mice.

Keywords:  POLG; aging; insulin resistance; metabolism; mitochondria; mitochondrial DNA; obesity

DOI:  https://doi.org/10.1111/acel.13166
Nat Commun. 2020 Oct 16. 11(1): 5261

Structure of inhibitor-bound mammalian complex I.

Hannah R Bridges, Justin G Fedor, James N Blaza, Andrea Di Luca, Alexander Jussupow, Owen D Jarman, John J Wright, Ahmed-Noor A Agip, Ana P Gamiz-Hernandez, Maxie M Roessler, Ville R I Kaila, Judy Hirst.

Respiratory complex I (NADH:ubiquinone oxidoreductase) captures the free energy from oxidising NADH and reducing ubiquinone to drive protons across the mitochondrial inner membrane and power oxidative phosphorylation. Recent cryo-EM analyses have produced near-complete models of the mammalian complex, but leave the molecular principles of its long-range energy coupling mechanism open to debate. Here, we describe the 3.0-Å resolution cryo-EM structure of complex I from mouse heart mitochondria with a substrate-like inhibitor, piericidin A, bound in the ubiquinone-binding active site. We combine our structural analyses with both functional and computational studies to demonstrate competitive inhibitor binding poses and provide evidence that two inhibitor molecules bind end-to-end in the long substrate binding channel. Our findings reveal information about the mechanisms of inhibition and substrate reduction that are central for understanding the principles of energy transduction in mammalian complex I.

DOI: https://doi.org/10.1038/s41467-020-18950-3
EBioMedicine. 2020 Oct 09. pii: S2352-3964(20)30426-6. [Epub ahead of print]61 103050

Impaired flickering of the permeability transition pore causes SPG7 spastic paraplegia.

Irene Sambri, Filomena Massa, Francesca Gullo, Simone Meneghini, Laura Cassina, Michela Carraro, Giorgia Dina, Angelo Quattrini, Lorenzo Patanella, Annamaria Carissimo, Antonella Iuliano, Filippo Santorelli, Franca Codazzi, Fabio Grohovaz, Paolo Bernardi, Andrea Becchetti, Giorgio Casari.

   BACKGROUND: Mutations of the mitochondrial protein paraplegin cause hereditary spastic paraplegia type 7 (SPG7), a so-far untreatable degenerative disease of the upper motoneuron with still undefined pathomechanism. The intermittent mitochondrial permeability transition pore (mPTP) opening, called flickering, is an essential process that operates to maintain mitochondrial homeostasis by reducing intra-matrix Ca2+ and reactive oxygen species (ROS) concentration, and is critical for efficient synaptic function.
METHODS: We use a fluorescence-based approach to measure mPTP flickering in living cells and biochemical and molecular biology techniques to dissect the pathogenic mechanism of SPG7. In the SPG7 animal model we evaluate the potential improvement of the motor defect, neuroinflammation and neurodegeneration by means of an mPTP inducer, the benzodiazepine Bz-423.
FINDINGS: We demonstrate that paraplegin is required for efficient transient opening of the mPTP, that is impaired in both SPG7 patients-derived fibroblasts and primary neurons from Spg7-/- mice. We show that dysregulation of mPTP opening at the pre-synaptic terminal impairs neurotransmitter release leading to ineffective synaptic transmission. Lack of paraplegin impairs mPTP flickering by a mechanism involving increased expression and activity of sirtuin3, which promotes deacetylation of cyclophilin D, thus hampering mPTP opening. Pharmacological treatment with Bz-423, which bypasses the activity of CypD, normalizes synaptic transmission and rescues the motor impairment of the SPG7 mouse model.
INTERPRETATION: mPTP targeting opens a new avenue for the potential therapy of this form of spastic paraplegia.
FUNDING: Telethon Foundation grant (TGMGCSBX16TT); Dept. of Defense, US Army, grant W81XWH-18-1-0001.

Keywords:  Hereditary spastic paraplegia; Mitochondria; Paraplegin; Permeability transition pore; SPG7; Synaptic vesicles

DOI:  https://doi.org/10.1016/j.ebiom.2020.103050
FASEB J. 2020 Oct 15.

Neuronal AMPK coordinates mitochondrial energy sensing and hypoxia resistance in C. elegans.

Brandon J Berry, Aksana Baldzizhar, Tyrone O Nieves, Andrew P Wojtovich.

  Organisms adapt to their environment through coordinated changes in mitochondrial function and metabolism. The mitochondrial protonmotive force (PMF) is an electrochemical gradient that powers ATP synthesis and adjusts metabolism to energetic demands via cellular signaling. It is unknown how or where transient PMF changes are sensed and signaled due to the lack of precise spatiotemporal control in vivo. We addressed this by expressing a light-activated proton pump in mitochondria to spatiotemporally "turn off" mitochondrial function through PMF dissipation in tissues with light. We applied our construct-mitochondria-OFF (mtOFF)-to understand how metabolic status impacts hypoxia resistance, a response that relies on mitochondrial function. Activation of mtOFF induced starvation-like behavior mediated by AMP-activated protein kinase (AMPK). We found prophylactic mtOFF activation increased survival following hypoxia, and that protection relied on neuronal AMPK. Our study links spatiotemporal control of mitochondrial PMF to cellular metabolic changes that mediate behavior and stress resistance.

Keywords:  anoxia; metabolism; optogenetics; uncoupling

DOI:  https://doi.org/10.1096/fj.202001150RR
Front Physiol. 2020 ;11 533683

Oxygen Glucose Deprivation Induced Prosurvival Autophagy Is Insufficient to Rescue Endothelial Function.

Venkateswaran Natarajan, Tania Mah, Chen Peishi, Shu Yi Tan, Ritu Chawla, Thiruma Valavan Arumugam, Adaikalavan Ramasamy, Karthik Mallilankaraman.

  Endothelial dysfunction, referring to a disturbance in the vascular homeostasis, has been implicated in many disease conditions including ischemic/reperfusion injury and atherosclerosis. Endothelial mitochondria have been increasingly recognized as a regulator of calcium homeostasis which has implications in the execution of diverse cellular events and energy production. The mitochondrial calcium uniporter complex through which calcium enters the mitochondria is composed of several proteins, including the pore-forming subunit MCU and its regulators MCUR1, MICU1, and MICU2. Mitochondrial calcium overload leads to opening of MPTP (mitochondrial permeability transition pore) and results in apoptotic cell death. Whereas, blockage of calcium entry into the mitochondria results in reduced ATP production thereby activates AMPK-mediated pro-survival autophagy. Here, we investigated the expression of mitochondrial calcium uniporter complex components (MCU, MCUR1, MICU1, and MICU2), induction of autophagy and apoptotic cell death in endothelial cells in response to oxygen-glucose deprivation. Human pulmonary microvascular endothelial cells (HPMVECs) were subjected to oxygen-glucose deprivation (OGD) at 3-h timepoints up to 12 h. Interestingly, except MCUR1 which was significantly downregulated, all other components of the uniporter (MCU, MICU1, and MICU2) remained unchanged. MCUR1 downregulation has been shown to activate AMPK mediated pro-survival autophagy. Similarly, MCUR1 downregulation in response to OGD resulted in AMPK phosphorylation and LC3 processing indicating the activation of pro-survival autophagy. Despite the activation of autophagy, OGD induced Caspase-mediated apoptotic cell death. Blockade of autophagy did not reduce OGD-induced apoptotic cell death whereas serum starvation conferred enough cellular and functional protection. In conclusion, the autophagic flux induced by MCUR1 downregulation in response to OGD is insufficient in protecting endothelial cells from undergoing apoptotic cell death and requires enhancement of autophagic flux by additional means such as serum starvation.

Keywords:  MCUR1; apoptotic cell death; autophagy; endothelial dysfunction; oxygen-glucose deprivation

DOI:  https://doi.org/10.3389/fphys.2020.533683
J Cell Biol. 2020 Nov 02. pii: e202003024. [Epub ahead of print]219(11):

MICOS subcomplexes assemble independently on the mitochondrial inner membrane in proximity to ER contact sites.

Parker S Tirrell, Kailey N Nguyen, Katherine Luby-Phelps, Jonathan R Friedman.

MICOS is a conserved multisubunit complex that localizes to mitochondrial cristae junctions and organizes cristae positioning within the organelle. MICOS is organized into two independent subcomplexes; however, the mechanisms that dictate the assembly and spatial positioning of each MICOS subcomplex are poorly understood. Here, we determine that MICOS subcomplexes target independently of one another to sites on the inner mitochondrial membrane that are in proximity to contact sites between mitochondria and the ER. One subcomplex, composed of Mic27/Mic26/Mic10/Mic12, requires ERMES complex function for its assembly. In contrast, the principal MICOS component, Mic60, self-assembles and localizes in close proximity to the ER through an independent mechanism. We also find that Mic60 can uniquely redistribute adjacent to forced mitochondria-vacuole contact sites. Our data suggest that nonoverlapping properties of interorganelle contact sites provide spatial cues that enable MICOS assembly and ultimately lead to proper physical and functional organization of mitochondria.

DOI: https://doi.org/10.1083/jcb.202003024
PLoS Genet. 2020 Oct 16. 16(10): e1009046

The Ccr4-Not complex regulates TORC1 signaling and mitochondrial metabolism by promoting vacuole V-ATPase activity.

Hongfeng Chen, P Winston Miller, Daniel L Johnson, R Nicholas Laribee.

The Ccr4-Not complex functions as an effector of multiple signaling pathways that control gene transcription and mRNA turnover. Consequently, Ccr4-Not contributes to a diverse array of processes, which includes a significant role in cell metabolism. Yet a mechanistic understanding of how it contributes to metabolism is lacking. Herein, we provide evidence that Ccr4-Not activates nutrient signaling through the essential target of rapamycin complex 1 (TORC1) pathway. Ccr4-Not disruption reduces global TORC1 signaling, and it also upregulates expression of the cell wall integrity (CWI) pathway terminal kinase Mpk1. Although CWI signaling represses TORC1 signaling, we find that Ccr4-Not loss inhibits TORC1 independently of CWI activation. Instead, we demonstrate that Ccr4-Not promotes the function of the vacuole V-ATPase, which interacts with the Gtr1 GTPase-containing EGO complex to stimulate TORC1 in response to nutrient sufficiency. Bypassing the V-ATPase requirement in TORC1 activation using a constitutively active Gtr1 mutant fully restores TORC1 signaling in Ccr4-Not deficient cells. Transcriptome analysis and functional studies revealed that loss of the Ccr4 subunit activates the TORC1 repressed retrograde signaling pathway to upregulate mitochondrial activity. Blocking this mitochondrial upregulation in Ccr4-Not deficient cells further represses TORC1 signaling, and it causes synergistic deficiencies in mitochondrial-dependent metabolism. These data support a model whereby Ccr4-Not loss impairs V-ATPase dependent TORC1 activation that forces cells to enhance mitochondrial metabolism to sustain a minimal level of TORC1 signaling necessary for cell growth and proliferation. Therefore, Ccr4-Not plays an integral role in nutrient signaling and cell metabolism by promoting V-ATPase dependent TORC1 activation.

DOI: https://doi.org/10.1371/journal.pgen.1009046
EMBO Rep. 2020 Oct 12. e50085

Chronic cold exposure enhances glucose oxidation in brown adipose tissue.

Zhichao Wang, Tinglu Ning, Anying Song, Jared Rutter, Qiong A Wang, Lei Jiang.

  The cultured brown adipocytes can oxidize glucose in vitro, but it is still not fully clear whether brown adipose tissue (BAT) could completely oxidize glucose in vivo. Although positron emission tomography (PET) with 18 F-fluorodeoxyglucose (18 F-FDG) showed a high level of glucose uptake in the activated BAT, the non-metabolizable 18 F-FDG cannot fully demonstrate intracellular glucose metabolism. Through in vivo [U-13 C]glucose tracing, here we show that chronic cold exposure dramatically activates glucose oxidation in BAT and the browning/beiging subcutaneous white adipose tissue (sWAT). Specifically, chronic cold exposure enhances glucose flux into the mitochondrial TCA cycle. Metabolic flux analysis models that β3-adrenergic receptor (β3-AR) agonist significantly enhances the flux of mitochondrial pyruvate uptake through mitochondrial pyruvate carrier (MPC) in the differentiated primary brown adipocytes. Furthermore, in vivo MPC inhibition blocks cold-induced glucose oxidation and impairs body temperature maintenance in mice. Together, mitochondrial pyruvate uptake and oxidation serve an important energy source in the chronic cold exposure activated BAT and beige adipose tissue, which supports a role for glucose oxidation in brown fat thermogenesis.

Keywords:  BAT; in vivo glucose tracing; metabolic flux analysis; mitochondrial pyruvate carrier

DOI:  https://doi.org/10.15252/embr.202050085
Science. 2020 Oct 16. pii: eaay8085. [Epub ahead of print]370(6514):

Mammalian lipid droplets are innate immune hubs integrating cell metabolism and host defense.

Marta Bosch, Miguel Sánchez-Álvarez, Alba Fajardo, Ronan Kapetanovic, Bernhard Steiner, Filipe Dutra, Luciana Moreira, Juan Antonio López, Rocío Campo, Montserrat Marí, Frederic Morales-Paytuví, Olivia Tort, Albert Gubern, Rachel M Templin, James E B Curson, Nick Martel, Cristina Català, Francisco Lozano, Francesc Tebar, Carlos Enrich, Jesús Vázquez, Miguel A Del Pozo, Matthew J Sweet, Patricia T Bozza, Steven P Gross, Robert G Parton, Albert Pol.

Lipid droplets (LDs) are the major lipid storage organelles of eukaryotic cells and a source of nutrients for intracellular pathogens. We demonstrate that mammalian LDs are endowed with a protein-mediated antimicrobial capacity, which is up-regulated by danger signals. In response to lipopolysaccharide (LPS), multiple host defense proteins, including interferon-inducible guanosine triphosphatases and the antimicrobial cathelicidin, assemble into complex clusters on LDs. LPS additionally promotes the physical and functional uncoupling of LDs from mitochondria, reducing fatty acid metabolism while increasing LD-bacterial contacts. Thus, LDs actively participate in mammalian innate immunity at two levels: They are both cell-autonomous organelles that organize and use immune proteins to kill intracellular pathogens as well as central players in the local and systemic metabolic adaptation to infection.

DOI: https://doi.org/10.1126/science.aay8085
Proc Natl Acad Sci U S A. 2020 Oct 14. pii: 202009943. [Epub ahead of print]

Functional interplay among thiol-based redox signaling, metabolism, and ferroptosis unveiled by a genetic variant of TP53.

Julia I-Ju Leu, Maureen E Murphy, Donna L George.

  The p53 tumor suppressor protein is a transcription factor and master stress response mediator, and it is subject to reduction-oxidation (redox)-dependent regulation. The P47S variant of TP53, which exists primarily in African-descent populations, associates with an elevated abundance of low molecular weight (LMW) thiols, including glutathione (GSH) and coenzyme A (CoA). Here we show that S47 and P47 cells exhibit distinct metabolic profiles, controlled by their different redox states and expression of Activating Transcription Factor-4 (ATF4). We find that S47 cells exhibit decreased catabolic glycolysis but increased use of the pentose phosphate pathway (PPP), and an enhanced abundance of the antioxidant, NADPH. We identify ATF4 as differentially expressed in P47 and S47 cells and show that ATF4 can reverse the redox status and rescue metabolism of S47 cells, as well as increase sensitivity to ferroptosis. This adaptive metabolic switch is rapid, reversible, and accompanied by thiol-mediated changes in the structures and activities of key glycolytic signaling pathway proteins, including GAPDH and G6PD. The results presented here unveil the important functional interplay among pathways regulating thiol-redox status, metabolic adaptation, and cellular responses to oxidative stress.

Keywords:  ATF4; coenzyme A; cysteine modifications; ferroptosis; p53

DOI:  https://doi.org/10.1073/pnas.2009943117
Cell Signal. 2020 Oct 08. pii: S0898-6568(20)30284-9. [Epub ahead of print]76 109807

Regulation of nutrient uptake by AMP-activated protein kinase.

Fatmah Alghamdi, Yazeed Alshuweishi, Ian P Salt.

  AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that is a key regulator of energy balance at both the cellular and whole-body level. AMPK acts to stimulate ATP production and reduce ATP consumption when cellular ATP levels fall, thereby normalizing energy balance. Given the central role of AMPK in cellular carbohydrate and lipid metabolism, AMPK activation has been proposed to be a therapeutic target for conditions associated with dysfunctional nutrient metabolism including obesity, type 2 diabetes, hepatic steatosis, cardiovascular diseases and cancer. One way by which increased ATP production can be achieved is by increasing the supply of nutrient substrates. In the 1990s, AMPK activation was demonstrated to stimulate glucose uptake in striated muscle, thereby improving substrate supply for ATP production. Subsequently AMPK activation was postulated to underlie the increase in glucose uptake that occurs during muscle contraction. More recently, however, several lines of evidence have demonstrated that AMPK activation is unlikely to be required for contraction-mediated glucose uptake. Furthermore, despite the importance of AMPK in cellular and whole-body metabolism, far fewer studies have investigated either the role of AMPK in glucose uptake by non-muscle tissues or whether AMPK regulates the uptake of fatty acids. In the present review, we discuss the role of AMPK in nutrient uptake by tissues, focusing on glucose uptake out with muscle and fatty acid uptake.

Keywords:  AMP-activated protein kinase; Fatty acid transport; Glucose transport; Lipogenesis

DOI:  https://doi.org/10.1016/j.cellsig.2020.109807
Proc Natl Acad Sci U S A. 2020 Oct 15. pii: 202010872. [Epub ahead of print]

Collective cancer cell invasion requires RNA accumulation at the invasive front.

George Chrisafis, Tianhong Wang, Konstadinos Moissoglu, Alexander N Gasparski, Yeap Ng, Roberto Weigert, Stephen J Lockett, Stavroula Mili.

  Localization of RNAs at protrusive regions of cells is important for single-cell migration on two-dimensional surfaces. Protrusion-enriched RNAs encode factors linked to cancer progression, such as the RAB13 GTPase and the NET1 guanine nucleotide exchange factor, and are regulated by the tumor-suppressor protein APC. However, tumor cells in vivo often do not move as single cells but rather utilize collective modes of invasion and dissemination. Here, we developed an inducible system of three-dimensional (3D) collective invasion to study the behavior and importance of protrusion-enriched RNAs. We find that, strikingly, both the RAB13 and NET1 RNAs are enriched specifically at the invasive front of leader cells in invasive cell strands. This localization requires microtubules and coincides with sites of high laminin concentration. Indeed, laminin association and integrin engagement are required for RNA accumulation at the invasive front. Importantly, perturbing RNA accumulation reduces collective 3D invasion. Examination of in vivo tumors reveals a similar localization of the RAB13 and NET1 RNAs at potential invasive sites, suggesting that this mechanism could provide a targeting opportunity for interfering with collective cancer cell invasion.

Keywords:  NET1; RAB13; RNA localization; antisense oligo; collective invasion

DOI:  https://doi.org/10.1073/pnas.2010872117
Biol Chem. 2020 Oct 01. pii: /j/bchm.just-accepted/hsz-2020-0286/hsz-2020-0286.xml. [Epub ahead of print]

Emerging roles for non-selenium containing ER-resident glutathione peroxidases in cell signaling and disease.

Katalin Buday, Marcus Conrad.

  Maintenance of cellular redox control is pivotal for normal cellular functions and cell fate decisions including cell death. Among the key cellular redox systems in mammals, the glutathione peroxidase (GPX) family of proteins is the largest conferring multifaceted functions and affecting virtually all cellular processes. The endoplasmic reticulum (ER)- resident glutathione peroxidases, designated as GPX7 and GPX8, are the most recently added members of this family of enzymes. Recent studies have provided exciting insights how both enzymes support critical processes of the ER including oxidative protein folding, maintenance of ER redox control, by eliminating H2O2, and preventing palmitic acid-induced lipotoxicity. Consequently, numerous pathological conditions, such as neurodegeneration, cancer and metabolic diseases have been linked with altered GPX7 and GPX8 expression. Studies in mice have demonstrated that loss of GPX7 leads to increased differentiation of preadipocytes, increased tumorigenesis and shortened lifespan. By contrast, GPX8 deficiency in mice results in enhanced caspase-4/11 activation and increased endotoxic shock in colitis model. With the increasing recognition that both types of enzymes are dysregulated in various tumor entities in man, we deem a review of the emerging roles played by GPX7 and GPX8 in health and disease development timely and appropriate.

Keywords:  Ca2+ signaling; ER stress; GPX; oxidative protein folding; oxidative stress

DOI:  https://doi.org/10.1515/hsz-2020-0286
J Biol Chem. 2020 10 15. pii: jbc.REV120.015101. [Epub ahead of print]

Visualizing, quantifying and manipulating mitochondrial DNA in vivo.

David L Prole, Patrick F Chinnery, Nick S Jones.

  Mitochondrial DNA (mtDNA) encodes proteins and RNAs that support the functions of mitochondria and thereby numerous physiological processes. Mutations of mtDNA can cause mitochondrial diseases and are implicated in ageing. The mtDNA within cells is organized into nucleoids within the mitochondrial matrix, but how mtDNA nucleoids are formed and regulated within cells remains incompletely resolved. Visualization of mtDNA within cells is a powerful means by which mechanistic insight can be gained. Manipulation of the amount, and sequence of, mtDNA within cells is important experimentally and for developing therapeutic interventions to treat mitochondrial disease. This review details recent developments and opportunities for improvements in the experimental tools and techniques that can be used to visualize, quantify and manipulate the properties of mtDNA within cells.

Keywords:  aging; gene editing; microscopy; mitochondria; mitochondrial DNA (mtDNA); mitochondrial disease; mitophagy

DOI:  https://doi.org/10.1074/jbc.REV120.015101
Metabolites. 2020 Oct 14. pii: E411. [Epub ahead of print]10(10):

Role of the Mitochondrial Pyruvate Carrier in the Occurrence of Metabolic Inflexibility in Drosophila melanogaster Exposed to Dietary Sucrose.

Chloé J Simard, Mohamed Touaibia, Eric Pierre Allain, Etienne Hebert-Chatelain, Nicolas Pichaud.

  Excess dietary carbohydrates are linked to dysregulation of metabolic pathways converging to mitochondria and metabolic inflexibility. Here, we determined the role of the mitochondrial pyruvate carrier (MPC) in the occurrence of this metabolic inflexibility in wild-type (WT) and MPC1-deficient (MPC1def) flies that were exposed to diets with different sucrose concentrations for 15-25 days (Standard Diet: SD, Medium-Sucrose Diet: MSD, and High-Sucrose Diet: HSD). Our results showed that MPC1def flies had lower mitochondrial respiration rates than WT flies on the SD and MSD. However, when exposed to the HSD, WT flies displayed decreased mitochondrial respiration rates compared to MPC1def flies. WT flies exposed to the HSD also displayed increased proline contribution and slightly decreased MPC1 expression. Surprisingly, when fed the MSD and the HSD, few metabolites were altered in WT flies whereas MPC1def flies display significant accumulation of glycogen, glucose, fructose, lactate, and glycerol. Overall, this suggests that metabolic inflexibility starts to occur in WT flies after 15-25 days of exposure to the HSD whereas the MPC1def flies display metabolic inflexibility independently of the diet provided. This study thus highlights the involvement of MPC as an essential protein in Drosophila to maintain proper metabolic homeostasis during changes in dietary resources.

Keywords:  Drosophila; homeostasis; metabolic inflexibility; metabolomics; mitochondrial pyruvate carrier; mitochondrial respiration; sucrose

DOI:  https://doi.org/10.3390/metabo10100411
Eur J Immunol. 2020 Oct 16.

Regulatory t cell metabolism at the intersection between autoimmune diseases and cancer.

Henry Kurniawan, Leticia Soriano-Baguet, Dirk Brenner.

  Regulatory T cells (Tregs) are critical for peripheral immune tolerance and homeostasis, and altered Treg behavior is involved in many pathologies, including autoimmunity and cancer. The expression of the transcription factor FoxP3 in Tregs is fundamental to maintaining their stability and immunosuppressive function. Recent studies have highlighted the crucial role that metabolic reprogramming plays in controlling Treg plasticity, stability and function. In this review, we summarize how the availability and use of various nutrients and metabolites influence Treg metabolic pathways and activity. We also discuss how Treg-intrinsic metabolic programs define and shape their differentiation, FoxP3 expression, and suppressive capacity. Lastly, we explore how manipulating the regulation of Treg metabolism might be exploited in different disease settings to achieve novel immunotherapies. This article is protected by copyright. All rights reserved.

Keywords:  Regulatory T cells; autoimmunity; cancer; metabolism

DOI:  https://doi.org/10.1002/eji.201948470
Trends Cancer. 2020 Oct 13. pii: S2405-8033(20)30261-2. [Epub ahead of print]

Cancer Plasticity: The Role of mRNA Translation.

Laura J Lee, David Papadopoli, Michael Jewer, Sonia Del Rincon, Ivan Topisirovic, Mitchell G Lawrence, Lynne-Marie Postovit.

  Tumor progression is associated with dedifferentiated histopathologies concomitant with cancer cell survival within a changing, and often hostile, tumor microenvironment. These processes are enabled by cellular plasticity, whereby intracellular cues and extracellular signals are integrated to enable rapid shifts in cancer cell phenotypes. Cancer cell plasticity, at least in part, fuels tumor heterogeneity and facilitates metastasis and drug resistance. Protein synthesis is frequently dysregulated in cancer, and emerging data suggest that translational reprograming collaborates with epigenetic and metabolic programs to effectuate phenotypic plasticity of neoplasia. Herein, we discuss the potential role of mRNA translation in cancer cell plasticity, highlight emerging histopathological correlates, and deliberate on how this is related to efforts to improve understanding of the complex tumor ecology.

Keywords:  cancer plasticity; mRNA translation; metabolism; protein synthesis; stromal–epithelial interactions; therapy resistance; tumor microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2020.09.005
Biochim Biophys Acta Bioenerg. 2020 Oct 13. pii: S0005-2728(20)30172-9. [Epub ahead of print] 148322

Inhibition of the mitochondrial ATPase function by IF1 changes the spatiotemporal organization of ATP synthase.

Verena Weissert, Bettina Rieger, Silke Morris, Tasnim Arroum, Olympia Ekaterini Psathaki, Thomas Zobel, Guy Perkins, Karin B Busch.



Keywords:  ATPase; F(1)F(O) ATP Synthase; IF1; IF1-H49K; OXPHOS; Opa1; Tracking And Localization Microscopy (TALM); inhibitory factor 1; mitochondria; mitochondrial ultrastructure; spatiotemporal organization; superresolution microscopy

DOI:  https://doi.org/10.1016/j.bbabio.2020.148322
Sci Adv. 2020 Oct;pii: eabb8941. [Epub ahead of print]6(42):

cGAS suppresses genomic instability as a decelerator of replication forks.

Hao Chen, Hao Chen, Jiamin Zhang, Yumin Wang, Antoine Simoneau, Hui Yang, Arthur S Levine, Lee Zou, Zhijian Chen, Li Lan.

The cyclic GMP-AMP synthase (cGAS), a sensor of cytosolic DNA, is critical for the innate immune response. Here, we show that loss of cGAS in untransformed and cancer cells results in uncontrolled DNA replication, hyperproliferation, and genomic instability. While the majority of cGAS is cytoplasmic, a fraction of cGAS associates with chromatin. cGAS interacts with replication fork proteins in a DNA binding-dependent manner, suggesting that cGAS encounters replication forks in DNA. Independent of cGAMP and STING, cGAS slows replication forks by binding to DNA in the nucleus. In the absence of cGAS, replication forks are accelerated, but fork stability is compromised. Consequently, cGAS-deficient cells are exposed to replication stress and become increasingly sensitive to radiation and chemotherapy. Thus, by acting as a decelerator of DNA replication forks, cGAS controls replication dynamics and suppresses replication-associated DNA damage, suggesting that cGAS is an attractive target for exploiting the genomic instability of cancer cells.

DOI: https://doi.org/10.1126/sciadv.abb8941
Science. 2020 Oct 16. 370(6514): 364-368

Comprehensive quantification of fuel use by the failing and nonfailing human heart.

Danielle Murashige, Cholsoon Jang, Michael Neinast, Jonathan J Edwards, Alexis Cowan, Matthew C Hyman, Joshua D Rabinowitz, David S Frankel, Zolt Arany.

The heart consumes circulating nutrients to fuel lifelong contraction, but a comprehensive mapping of human cardiac fuel use is lacking. We used metabolomics on blood from artery, coronary sinus, and femoral vein in 110 patients with or without heart failure to quantify the uptake and release of 277 metabolites, including all major nutrients, by the human heart and leg. The heart primarily consumed fatty acids and, unexpectedly, little glucose; secreted glutamine and other nitrogen-rich amino acids, indicating active protein breakdown, at a rate ~10 times that of the leg; and released intermediates of the tricarboxylic acid cycle, balancing anaplerosis from amino acid breakdown. Both heart and leg consumed ketones, glutamate, and acetate in direct proportionality to circulating levels, indicating that availability is a key driver for consumption of these substrates. The failing heart consumed more ketones and lactate and had higher rates of proteolysis. These data provide a comprehensive and quantitative picture of human cardiac fuel use.

DOI: https://doi.org/10.1126/science.abc8861
Nat Metab. 2020 Oct 12.

Mind your media.

Shoval Lagziel, Eyal Gottlieb, Tomer Shlomi.

DOI: https://doi.org/10.1038/s42255-020-00299-y
Biochemistry (Mosc). 2020 Jul;85(7): 801-807

Regulation of Thiamine (Vitamin B1)-Dependent Metabolism in Mammals by p53.

V I Bunik, V A Aleshin, X Zhou, S Krishnan, A Karlsson.

Transcriptional factor p53 is a master regulator of energy metabolism. Energy metabolism strongly depends on thiamine (vitamin B1) and/or its natural derivatives. Thiamine diphosphate (ThDP), which is a major thiamine derivative, affects p53 binding to DNA. In order to elucidate the mechanism of regulation of thiamine-dependent metabolism by p53, we assessed putative p53-binding sites near transcription starting points in genes coding for transporters and enzymes, whose function is associated with thiamine and/or its derivatives. The predictions were validated by studying cell metabolic response to the p53 inducer cisplatin. Expression of p53 and its known target, p21, has been evaluated in cisplatin-treated and control human lung adenocarcinoma A549 cells that possess functional p53 pathway. We also investigated the activity of enzymes involved in the thiamine-dependent energy metabolism. Along with upregulating the expression of p53 and p21, cisplatin affected the activities of metabolic enzymes, whose genes were predicted as carrying the p53-binding sites. The activity of glutamate dehydrogenase GDH2 isoenzyme strongly decreased, while the activities of NADP+-dependent isocitrate dehydrogenase (IDH) and malic enzymes, as well as the activity of 2-oxoglutarate dehydrogenase complex at its endogenous ThDP level, were elevated. Simultaneously, the activities of NAD+-dependent IDH, mitochondrial aspartate aminotransferase, and two malate dehydrogenase isoenzymes, whose genes were not predicted to have the p53-binding sequences near the transcription starting points, were upregulated by cisplatin. The p53-dependent regulation of the assayed metabolic enzymes correlated with induction of p21 by p53 rather than induction of p53 itself.

DOI: https://doi.org/10.1134/S0006297920070081
Nat Commun. 2020 10 14. 11(1): 5156

Pan-cancer analysis reveals TAp63-regulated oncogenic lncRNAs that promote cancer progression through AKT activation.

Marco Napoli, Xiaobo Li, Hayley D Ackerman, Avani A Deshpande, Ivan Barannikov, Marlese A Pisegna, Isabelle Bedrosian, Jürgen Mitsch, Philip Quinlan, Alastair Thompson, Kimal Rajapakshe, Cristian Coarfa, Preethi H Gunaratne, Douglas C Marchion, Anthony M Magliocco, Kenneth Y Tsai, Elsa R Flores.

The most frequent genetic alterations across multiple human cancers are mutations in TP53 and the activation of the PI3K/AKT pathway, two events crucial for cancer progression. Mutations in TP53 lead to the inhibition of the tumour and metastasis suppressor TAp63, a p53 family member. By performing a mouse-human cross species analysis between the TAp63 metastatic mammary adenocarcinoma mouse model and models of human breast cancer progression, we identified two TAp63-regulated oncogenic lncRNAs, TROLL-2 and TROLL-3. Further, using a pan-cancer analysis of human cancers and multiple mouse models of tumour progression, we revealed that these two lncRNAs induce the activation of AKT to promote cancer progression by regulating the nuclear to cytoplasmic translocation of their effector, WDR26, via the shuttling protein NOLC1. Our data provide preclinical rationale for the implementation of these lncRNAs and WDR26 as therapeutic targets for the treatment of human tumours dependent upon mutant TP53 and/or the PI3K/AKT pathway.

DOI: https://doi.org/10.1038/s41467-020-18973-w
Nat Rev Endocrinol. 2020 Oct 16.

The role of stress kinases in metabolic disease.

Ivana Nikolic, Magdalena Leiva, Guadalupe Sabio.

Obesity is a health condition that has reached pandemic levels and is implicated in the development and progression of type 2 diabetes mellitus, cancer and heart failure. A key characteristic of obesity is the activation of stress-activated protein kinases (SAPKs), such as the p38 and JNK stress kinases, in several organs, including adipose tissue, liver, skeletal muscle, immune organs and the central nervous system. The correct timing, intensity and duration of SAPK activation contributes to cellular metabolic adaptation. By contrast, uncontrolled SAPK activation has been proposed to contribute to the complications of obesity. The stress kinase signalling pathways have therefore been identified as potential targets for the development of novel therapeutic approaches for metabolic syndrome. The past few decades have seen intense research efforts to determine how these kinases are regulated in a cell-specific manner and to define their contribution to the development of obesity and insulin resistance. Several studies have uncovered new and unexpected functions of the non-classical members of both pathways. Here, we provide an overview of the role of SAPKs in metabolic control and highlight important discoveries in the field.

DOI: https://doi.org/10.1038/s41574-020-00418-5
Science. 2020 Oct 16. 370(6514): 351-356

The GATOR-Rag GTPase pathway inhibits mTORC1 activation by lysosome-derived amino acids.

Geoffrey G Hesketh, Fotini Papazotos, Judy Pawling, Dushyandi Rajendran, James D R Knight, Sebastien Martinez, Mikko Taipale, Daniel Schramek, James W Dennis, Anne-Claude Gingras.

The mechanistic target of rapamycin complex 1 (mTORC1) couples nutrient sufficiency to cell growth. mTORC1 is activated by exogenously acquired amino acids sensed through the GATOR-Rag guanosine triphosphatase (GTPase) pathway, or by amino acids derived through lysosomal degradation of protein by a poorly defined mechanism. Here, we revealed that amino acids derived from the degradation of protein (acquired through oncogenic Ras-driven macropinocytosis) activate mTORC1 by a Rag GTPase-independent mechanism. mTORC1 stimulation through this pathway required the HOPS complex and was negatively regulated by activation of the GATOR-Rag GTPase pathway. Therefore, distinct but functionally coordinated pathways control mTORC1 activity on late endocytic organelles in response to distinct sources of amino acids.

DOI: https://doi.org/10.1126/science.aaz0863
Cell. 2020 Oct 14. pii: S0092-8674(20)31241-1. [Epub ahead of print]

Targeting KRAS(G12C): From Inhibitory Mechanism to Modulation of Antitumor Effects in Patients.

Dongsung Kim, Jenny Yaohua Xue, Piro Lito.

KRAS mutations are among the most common genetic alterations in lung, colorectal, and pancreatic cancers. Direct inhibition of KRAS oncoproteins has been a long-standing pursuit in precision oncology, one established shortly after the discovery of RAS mutations in human cancer cells nearly 40 years ago. Recent advances in medicinal chemistry have established inhibitors targeting KRAS(G12C), a mutation found in ∼13% of lung adenocarcinomas and, at a lower frequency, in other cancers. Preclinical studies describing their discovery and mechanism of action, coupled with emerging clinical data from patients treated with these drugs, have sparked a renewed enthusiasm in the study of KRAS and its therapeutic potential. Here, we discuss how these advances are reshaping the fundamental aspects of KRAS oncoprotein biology and the strides being made toward improving patient outcomes in the clinic.

DOI: https://doi.org/10.1016/j.cell.2020.09.044