bims-camemi 2019-04-28 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2019–04–28
twenty-six papers selected by
Christian Frezza, , University of Cambridge, MRC Cancer Unit

ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes through the PERK-eIF2α Axis.
Cell-autonomous and non-autonomous roles of daf-16 in muscle function and mitochondrial capacity in aging C. elegans.
Mitochondrial Quality Control in Aging and Heart Failure: Influence of Ketone Bodies and Mitofusin-Stabilizing Peptides.
Metabolic alterations and the potential for targeting metabolic pathways in the treatment of multiple myeloma.
Mitofusin 2 Participates in Mitophagy and Mitochondrial Fusion Against Angiotensin II-Induced Cardiomyocyte Injury.
The Fine Tuning of Drp1-Dependent Mitochondrial Remodeling and Autophagy Controls Neuronal Differentiation.
Time of Exercise Specifies the Impact on Muscle Metabolic Pathways and Systemic Energy Homeostasis.
NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling.
Regulation of Autophagy by Nuclear GAPDH and Its Aggregates in Cancer and Neurodegenerative Disorders.
Metabolic basis of brain-like electrical signalling in bacterial communities.
A novel pathogenic m.4412G>A MT-TM mitochondrial DNA variant associated with childhood-onset seizures, myopathy and bilateral basal ganglia changes.
The cyclooxygenase-1/mPGES-1/endothelial prostaglandin EP4 receptor pathway constrains myocardial ischemia-reperfusion injury.
ERRα as a Bridge Between Transcription and Function: Role in Liver Metabolism and Disease.
Cystine-glutamate antiporter xCT deficiency suppresses tumor growth while preserving antitumor immunity.
Depletion of ATP-Citrate Lyase (ATPCL) Affects Chromosome Integrity Without Altering Histone Acetylation in Drosophila Mitotic Cells.
Metabolic profiling of cancer cells reveals genome-wide crosstalk between transcriptional regulators and metabolism.
Autophagy, Apoptosis, and Mitochondria: Molecular Integration and Physiological Relevance in Skeletal Muscle.
Bile Acids as Metabolic Regulators and Nutrient Sensors.
Multiplexed imaging for diagnosis and therapy.
Succinate Dehydrogenase-Deficient Renal Cell Carcinoma.
Vulnerabilities in mIDH2 AML confer sensitivity to APL-like targeted combination therapy.
The Crosstalk Between Cell Adhesion and Cancer Metabolism.
Sensory primary cilium is a responsive cAMP microdomain in renal epithelia.
Interrogating metabolism as an electron flow system.
A fat-tissue sensor couples growth to oxygen availability by remotely controlling insulin secretion.
Mic60 exhibits a coordinated clustered distribution along and across yeast and mammalian mitochondria.

Mol Cell. 2019 Apr 13. pii: S1097-2765(19)30235-7. [Epub ahead of print]

ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes through the PERK-eIF2α Axis.

Eduardo Balsa, Meghan S Soustek, Ajith Thomas, Sara Cogliati, Carolina García-Poyatos, Elena Martín-García, Mark Jedrychowski, Steve P Gygi, José Antonio Enriquez, Pere Puigserver.

  Endoplasmic reticulum (ER) stress and unfolded protein response are energetically challenging under nutrient stress conditions. However, the regulatory mechanisms that control the energetic demand under nutrient and ER stress are largely unknown. Here we show that ER stress and glucose deprivation stimulate mitochondrial bioenergetics and formation of respiratory supercomplexes (SCs) through protein kinase R-like ER kinase (PERK). Genetic ablation or pharmacological inhibition of PERK suppresses nutrient and ER stress-mediated increases in SC levels and reduces oxidative phosphorylation-dependent ATP production. Conversely, PERK activation augments respiratory SCs. The PERK-eIF2α-ATF4 axis increases supercomplex assembly factor 1 (SCAF1 or COX7A2L), promoting SCs and enhanced mitochondrial respiration. PERK activation is sufficient to rescue bioenergetic defects caused by complex I missense mutations derived from mitochondrial disease patients. These studies have identified an energetic communication between ER and mitochondria, with implications in cell survival and diseases associated with mitochondrial failures.

Keywords:  ATF4; ER stress; PERK; hexosamine pathway; mitochondria; mitochondrial cristae; mitochondrial diseases; nutrient stress; protein glycosylation; respiratory chain supercomplexes

DOI:  https://doi.org/10.1016/j.molcel.2019.03.031
Aging (Albany NY). 2019 Apr 24.

Cell-autonomous and non-autonomous roles of daf-16 in muscle function and mitochondrial capacity in aging C. elegans.

Hongning Wang, Phillip Webster, Lizhen Chen, Alfred L Fisher.

  Sarcopenia, defined as the loss of skeletal muscle mass and strength, contributes to disability and health-related conditions with aging. In vitro studies indicate that age-related mitochondrial dysfunction could play a central role in the development and progression of sarcopenia, but because of limitations in the methods employed, how aging affects muscle mitochondrial function in vivo is not fully understood. We use muscle-targeted fluorescent proteins and the ratiometric ATP reporter, ATeam, to examine changes in muscle mitochondrial mass and morphology, and intracellular ATP levels in C. elegans. We find that the preserved muscle function in aging daf-2 mutants is associated with higher muscle mitochondrial mass, preserved mitochondrial morphology, and higher levels of intracellular ATP. These phenotypes require the daf-16/FOXO transcription factor. Via the tissue-specific rescue of daf-16, we find that daf-16 activity in either muscle or neurons is sufficient to enhance muscle mitochondrial mass, whereas daf-16 activity in the muscle is required for the enhanced muscle function and mobility of the daf-2 mutants. Finally, we show through the use of drugs known to enhance mitochondrial activity that augmenting mitochondrial function leads to improved mobility during aging. These results suggest an important role for mitochondrial function in muscle aging.

Keywords:  aging; daf-16; daf-2; mitochondria; muscle

DOI:  https://doi.org/10.18632/aging.101914
Front Physiol. 2019 ;10 382

Mitochondrial Quality Control in Aging and Heart Failure: Influence of Ketone Bodies and Mitofusin-Stabilizing Peptides.

Phung N Thai, Lea K Seidlmayer, Charles Miller, Maura Ferrero, Gerald W Dorn Ii, Saul Schaefer, Donald M Bers, Elena N Dedkova.

  Aim: Aging and heart failure (HF) are each characterized by increased mitochondrial damage, which may contribute to further cardiac dysfunction. Mitophagy in response to mitochondrial damage can improve cardiovascular health. HF is also characterized by increased formation and consumption of ketone bodies (KBs), which may activate mitophagy and provide an endogenous mechanism to limit the adverse effects of mitochondrial damage. However, the role of KBs in activation of mitophagy in aging and HF has not been evaluated. Methods: We assessed mitophagy by measuring mitochondrial Parkin accumulation and LC3-mediated autophagosome formation in cardiomyocytes from young (2.5 months), aged (2.5 years), and aged rabbits with HF (2.5 years) induced by aortic insufficiency and stenosis. Levels of reactive oxygen species (ROS) generation and redox balance were monitored using genetically encoded sensors ORP1-roGFP2 and GRX1-roGFP2, targeted to mitochondrial or cytosolic compartments, respectively. Results: Young rabbits exhibited limited mitochondrial Parkin accumulation with small (~1 μm2) puncta. Those small Parkin puncta increased four-fold in aged rabbit hearts, accompanied by elevated LC3-mediated autophagosome formation. HF hearts exhibited fewer small puncta, but many very large Parkin-rich regions (4-5 μm2) with completely depolarized mitochondria. Parkin protein expression was barely detectable in young animals and was much higher in aged and maximal in HF hearts. Expression of mitofusin 2 (MFN2) and dynamin-related protein 1 (DRP1) was reduced by almost 50% in HF, consistent with improper fusion-fission, contributing to mitochondrial Parkin build-up. The KB β-hydroxybutyrate (β-OHB) enhanced mitophagy in young and aging myocytes, but not in HF where β-OHB further increased the number of cells with giant Parkin-rich regions. This β-OHB effect on Parkin-rich areas was prevented by cell-permeable TAT-MP1Gly peptide (thought to promote MFN2-dependent fusion). Basal levels of mitochondrial ROS were highest in HF, while cytosolic ROS was highest in aged compared to HF myocytes, suggesting that cytosolic ROS promotes Parkin recruitment to the mitochondria. Conclusion: We conclude that elevated KB levels were beneficial for mitochondrial repair in the aging heart. However, an impaired MFN2-DRP1-mediated fusion-fission process in HF reduced this benefit, as well as Parkin degradation and mitophagic signaling cascade.

Keywords:  Parkin; aging; heart failure; ketone bodies; mitochondrial quality control; mitofusin; mitophagy; β-hydroxybutyrate

DOI:  https://doi.org/10.3389/fphys.2019.00382
J Cancer Metastasis Treat. 2019 ;pii: 26. [Epub ahead of print]5

Metabolic alterations and the potential for targeting metabolic pathways in the treatment of multiple myeloma.

Dustin Rizzieri, Barry Paul, Yubin Kang.

  Metabolism is defined as the collection of complex biochemical processes that living cells use to generate energy and maintain their growth and survival. Metabolism encompasses the synthesis and breakdown of glucose, fatty acids, and amino acids; the generation of energy (ATP); and oxidative phosphorylation. In cancer cells, metabolism can be commandeered to promote tumor growth and cellular proliferation. These alterations in metabolism have emerged as an additional hallmark of various cancers. In this review we focus on metabolic alterations in multiple myeloma (MM) - a malignancy of plasma cells - including derangements in glycolysis, gluconeogenesis, the tricarboxylic acid cycle, oxidative phosphorylation, and fatty acid/amino acid synthesis and degradation. Particular focus is given to metabolic alterations that contribute to myeloma cell growth, proliferation and drug resistance. Finally, novel approaches that target metabolic pathways for the treatment of MM are discussed.

Keywords:  Metabolism; alterations; multiple myeloma; treatment

DOI:  https://doi.org/10.20517/2394-4722.2019.05
Front Physiol. 2019 ;10 411

Mitofusin 2 Participates in Mitophagy and Mitochondrial Fusion Against Angiotensin II-Induced Cardiomyocyte Injury.

Wenjun Xiong, Zhuang Ma, Dongqi An, Zuheng Liu, Wanqiang Cai, Yujia Bai, Qiong Zhan, Wenyan Lai, Qingchun Zeng, Hao Ren, Dingli Xu.

   Background: Mitochondrial dynamics play a critical role in mitochondrial function. The mitofusin 2 (MFN2) gene encodes a mitochondrial membrane protein that participates in mitochondrial fusion to maintain and operate the mitochondrial network. Moreover, MFN2 is essential for mitophagy. In Ang II-induced cardiac remodeling, the combined effects of MFN2-mediated mitochondrial fusion and mitophagy are unclear. This study was designed to explore a novel strategy for preventing cardiomyocyte injury via modulation of mitochondrial dynamics.
Methods: We studied the function of MFN2 in mitochondrial fusion and mitophagy in Ang II-stimulated cardiomyocyte injury. Cardiomyocyte injury experiments, including reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), and apoptosis rate of cardiomyocytes were performed. The mitochondrial morphology in cardiomyocytes was examined via transmission electron microscopy (TEM) and confocal microscopy. Autophagic levels in response to Ang II were examined by immunoblotting of autophagy-related proteins. Moreover, PINK1/MFN2/Parkin pathway-related proteins were examined.
Results: With stimulation by Ang II, MFN2 expression was progressively reduced. MFN2 deficiency impaired mitochondrial quality, resulting in exacerbated mitochondrial damage induced by Ang II. The Ang II-induced increases in ROS production and apoptosis rate were alleviated by MFN2 overexpression. Moreover, MFN2 alleviated the Ang II-induced reduction in MMP. MFN2 promoted mitochondrial fusion, and MFN2 promoted Parkin translocation and phosphorylation, leading to mitochondrial autophagy. The effects of MFN2 overexpression were reversed by autophagy inhibitors.
Conclusion: Mitofusin 2 promotes Parkin translocation and phosphorylation, leading to mitophagy to clear damaged mitochondria. However, the beneficial effects of MFN2 were reversed by autophagy inhibitors. Additionally, MFN2 participates in mitochondrial fusion to maintain mitochondrial quality. Thus, MFN2 participated in mitophagy and mitochondrial fusion against Ang II-induced cardiomyocyte injury.

Keywords:  MFN2; ROS; angiotensin II; autophagy; mitochondria

DOI:  https://doi.org/10.3389/fphys.2019.00411
Front Cell Neurosci. 2019 ;13 120

The Fine Tuning of Drp1-Dependent Mitochondrial Remodeling and Autophagy Controls Neuronal Differentiation.

Chiara Vantaggiato, Marianna Castelli, Matteo Giovarelli, Genny Orso, Maria Teresa Bassi, Emilio Clementi, Clara De Palma.

  Mitochondria play a critical role in neuronal function and neurodegenerative disorders, including Alzheimer's, Parkinson's and Huntington diseases and amyotrophic lateral sclerosis, that show mitochondrial dysfunctions associated with excessive fission and increased levels of the fission protein dynamin-related protein 1 (Drp1). Our data demonstrate that Drp1 regulates the transcriptional program induced by retinoic acid (RA), leading to neuronal differentiation. When Drp1 was overexpressed, mitochondria underwent remodeling but failed to elongate and this enhanced autophagy and apoptosis. When Drp1 was blocked during differentiation by overexpressing the dominant negative form or was silenced, mitochondria maintained the same elongated shape, without remodeling and this increased cell death. The enhanced apoptosis, observed with both fragmented or elongated mitochondria, was associated with increased induction of unfolded protein response (UPR) and ER-associated degradation (ERAD) processes that finally affect neuronal differentiation. These findings suggest that physiological fission and mitochondrial remodeling, associated with early autophagy induction are essential for neuronal differentiation. We thus reveal the importance of mitochondrial changes to generate viable neurons and highlight that, rather than multiple parallel events, mitochondrial changes, autophagy and apoptosis proceed in a stepwise fashion during neuronal differentiation affecting the nuclear transcriptional program.

Keywords:  Drp1; autophagy; mitochondrial fission; mitochondrial remodeling; neuronal differentiation

DOI:  https://doi.org/10.3389/fncel.2019.00120
Cell Metab. 2019 Apr 12. pii: S1550-4131(19)30183-4. [Epub ahead of print]

Time of Exercise Specifies the Impact on Muscle Metabolic Pathways and Systemic Energy Homeostasis.

Shogo Sato, Astrid Linde Basse, Milena Schönke, Siwei Chen, Muntaha Samad, Ali Altıntaş, Rhianna C Laker, Emilie Dalbram, Romain Barrès, Pierre Baldi, Jonas T Treebak, Juleen R Zierath, Paolo Sassone-Corsi.

  While the timing of food intake is important, it is unclear whether the effects of exercise on energy metabolism are restricted to unique time windows. As circadian regulation is key to controlling metabolism, understanding the impact of exercise performed at different times of the day is relevant for physiology and homeostasis. Using high-throughput transcriptomic and metabolomic approaches, we identify distinct responses of metabolic oscillations that characterize exercise in either the early rest phase or the early active phase in mice. Notably, glycolytic activation is specific to exercise at the active phase. At the molecular level, HIF1α, a central regulator of glycolysis during hypoxia, is selectively activated in a time-dependent manner upon exercise, resulting in carbohydrate exhaustion, usage of alternative energy sources, and adaptation of systemic energy expenditure. Our findings demonstrate that the time of day is a critical factor to amplify the beneficial impact of exercise on both metabolic pathways within skeletal muscle and systemic energy homeostasis.

Keywords:  HIF1α; circadian rhythms; energy homeostasis; exercise metabolism; glycolysis; lipid oxidation; metabolomics; skeletal muscle; transcriptomics

DOI:  https://doi.org/10.1016/j.cmet.2019.03.013
Nature. 2019 Apr 24.

NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling.

Sudhir Chowdhry, Ciro Zanca, Utkrisht Rajkumar, Tomoyuki Koga, Yarui Diao, Ramya Raviram, Feng Liu, Kristen Turner, Huijun Yang, Elizabeth Brunk, Junfeng Bi, Frank Furnari, Vineet Bafna, Bing Ren, Paul S Mischel.

Precision oncology hinges on linking tumour genotype with molecularly targeted drugs1; however, targeting the frequently dysregulated metabolic landscape of cancer has proven to be a major challenge2. Here we show that tissue context is the major determinant of dependence on the nicotinamide adenine dinucleotide (NAD) metabolic pathway in cancer. By analysing more than 7,000 tumours and 2,600 matched normal samples of 19 tissue types, coupled with mathematical modelling and extensive in vitro and in vivo analyses, we identify a simple and actionable set of 'rules'. If the rate-limiting enzyme of de novo NAD synthesis, NAPRT, is highly expressed in a normal tissue type, cancers that arise from that tissue will have a high frequency of NAPRT amplification and be completely and irreversibly dependent on NAPRT for survival. By contrast, tumours that arise from normal tissues that do not express NAPRT highly are entirely dependent on the NAD salvage pathway for survival. We identify the previously unknown enhancer that underlies this dependence. Amplification of NAPRT is shown to generate a pharmacologically actionable tumour cell dependence for survival. Dependence on another rate-limiting enzyme of the NAD synthesis pathway, NAMPT, as a result of enhancer remodelling is subject to resistance by NMRK1-dependent synthesis of NAD. These results identify a central role for tissue context in determining the choice of NAD biosynthetic pathway, explain the failure of NAMPT inhibitors, and pave the way for more effective treatments.

DOI: https://doi.org/10.1038/s41586-019-1150-2
Int J Mol Sci. 2019 Apr 26. pii: E2062. [Epub ahead of print]20(9):

Regulation of Autophagy by Nuclear GAPDH and Its Aggregates in Cancer and Neurodegenerative Disorders.

Giovanna Butera, Nidula Mullappilly, Francesca Masetto, Marta Palmieri, Maria Teresa Scupoli, Raffaella Pacchiana, Massimo Donadelli.

  Several studies indicate that the cytosolic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has pleiotropic functions independent of its canonical role in glycolysis. The GAPDH functional diversity is mainly due to post-translational modifications in different amino acid residues or due to protein-protein interactions altering its localization from cytosol to nucleus, mitochondria or extracellular microenvironment. Non-glycolytic functions of GAPDH include the regulation of cell death, autophagy, DNA repair and RNA export, and they are observed in physiological and pathological conditions as cancer and neurodegenerative disorders. In disease, the knowledge of the mechanisms regarding GAPDH-mediated cell death is becoming fundamental for the identification of novel therapies. Here, we elucidate the correlation between autophagy and GAPDH in cancer, describing the molecular mechanisms involved and its impact in cancer development. Since autophagy is a degradative pathway associated with the regulation of cell death, we discuss recent evidence supporting GAPDH as a therapeutic target for autophagy regulation in cancer therapy. Furthermore, we summarize the molecular mechanisms and the cellular effects of GAPDH aggregates, which are correlated with mitochondrial malfunctions and can be considered a potential therapeutic target for various diseases, including cancer and neurodegenerative disorders.

Keywords:  GAPDH; aggregates; autophagy; cancer; cell death

DOI:  https://doi.org/10.3390/ijms20092062
Philos Trans R Soc Lond B Biol Sci. 2019 Jun 10. 374(1774): 20180382

Metabolic basis of brain-like electrical signalling in bacterial communities.

Rosa Martinez-Corral, Jintao Liu, Arthur Prindle, Gürol M Süel, Jordi Garcia-Ojalvo.

  Information processing in the mammalian brain relies on a careful regulation of the membrane potential dynamics of its constituent neurons, which propagates across the neuronal tissue via electrical signalling. We recently reported the existence of electrical signalling in a much simpler organism, the bacterium Bacillus subtilis. In dense bacterial communities known as biofilms, nutrient-deprived B. subtilis cells in the interior of the colony use electrical communication to transmit stress signals to the periphery, which interfere with the growth of peripheral cells and reduce nutrient consumption, thereby relieving stress from the interior. Here, we explicitly address the interplay between metabolism and electrophysiology in bacterial biofilms, by introducing a spatially extended mathematical model that combines the metabolic and electrical components of the phenomenon in a discretized reaction-diffusion scheme. The model is experimentally validated by environmental and genetic perturbations, and confirms that metabolic stress is transmitted through the bacterial population via a potassium wave. Interestingly, this behaviour is reminiscent of cortical spreading depression in the brain, characterized by a wave of electrical activity mediated by potassium diffusion that has been linked to various neurological disorders, calling for future studies on the evolutionary link between the two phenomena. This article is part of the theme issue 'Liquid brains, solid brains: How distributed cognitive architectures process information'.

Keywords:  bacterial biofilms; cellular excitability; electrical signalling; membrane potential; potassium waves

DOI:  https://doi.org/10.1098/rstb.2018.0382
Mitochondrion. 2019 Apr 22. pii: S1567-7249(19)30068-6. [Epub ahead of print]

A novel pathogenic m.4412G>A MT-TM mitochondrial DNA variant associated with childhood-onset seizures, myopathy and bilateral basal ganglia changes.

Albert Lim, Emma L Blakely, Karen Baty, Langping He, Sila Hopton, Gavin Falkous, Kenneth McWilliam, Alison Cozens, Robert McFarland, Robert W Taylor.

  Mitochondrial DNA variants in the MT-TM (mt-tRNAMet) gene are rare, typically associated with myopathic phenotypes. We identified a novel MT-TM variant resulting in prolonged seizures with childhood-onset myopathy, retinopathy, short stature and elevated CSF lactate associated with bilateral basal ganglia changes on neuroimaging. Muscle biopsy confirmed multiple respiratory chain deficiencies and focal cytochrome c oxidase (COX) histochemical abnormalities. Next-generation sequencing of the mitochondrial genome revealed a novel m.4412G>A variant at high heteroplasmy levels in muscle that fulfils all accepted criteria for pathogenicity including segregation within single muscle fibres, thus broadening the genotypic and phenotypic landscape of mitochondrial tRNA-related disease.

Keywords:  Basal ganglia changes; MTTM; Mitochondrial disease; Myopathy; Seizures; mtDNA variant

DOI:  https://doi.org/10.1016/j.mito.2019.04.007
Nat Commun. 2019 Apr 23. 10(1): 1888

The cyclooxygenase-1/mPGES-1/endothelial prostaglandin EP4 receptor pathway constrains myocardial ischemia-reperfusion injury.

Liyuan Zhu, Chuansheng Xu, Xingyu Huo, Huifeng Hao, Qing Wan, Hong Chen, Xu Zhang, Richard M Breyer, Yu Huang, Xuetao Cao, De-Pei Liu, Garret A FitzGerald, Miao Wang.

The use of nonsteroidal anti-inflammatory drugs that inhibit cyclooxygenase (COX)-1 and COX-2, increases heart failure risk. It is unknown whether microsomal (m) prostaglandin (PG) E synthase (S)-1, a target downstream of COX, regulates myocardial (M) ischemia/reperfusion (I/R) injury, a key determinant of heart failure. Here we report that COX-1 and mPGES-1 mediate production of substantial amounts of PGE2 and confer cardiac protection in MI/R. Deletion of mPges-1 impairs cardiac microvascular perfusion and increases inflammatory cell infiltration in mouse MI/R. Consistently, mPges-1 deletion depresses the arteriolar dilatory response to I/R in vivo and to acetylcholine ex vivo, and enhances leukocyte-endothelial cell interaction, which is mediated via PGE receptor-4 (EP4). Furthermore, endothelium-restricted Ep4 deletion impairs microcirculation, and exacerbates MI/R injury, irrespective of EP4 agonism. Treatment with misoprostol, a clinically available PGE analogue, improves microcirculation and reduces MI/R injury. Thus, mPGES-1, a key microcirculation protector, constrains MI/R injury and this beneficial effect is partially mediated via endothelial EP4.

DOI: https://doi.org/10.1038/s41467-019-09492-4
Front Endocrinol (Lausanne). 2019 ;10 206

ERRα as a Bridge Between Transcription and Function: Role in Liver Metabolism and Disease.

Hui Xia, Catherine R Dufour, Vincent Giguère.

  As transcriptional factors, nuclear receptors (NRs) function as major regulators of gene expression. In particular, dysregulation of NR activity has been shown to significantly alter metabolic homeostasis in various contexts leading to metabolic disorders and cancers. The orphan estrogen-related receptor (ERR) subfamily of NRs, comprised of ERRα, ERRβ, and ERRγ, for which a natural ligand has yet to be identified, are known as central regulators of energy metabolism. If AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) can be viewed as sensors of the metabolic needs of a cell and responding acutely via post-translational control of proteins, then the ERRs can be regarded as downstream effectors of metabolism via transcriptional regulation of genes for a long-term and sustained adaptive response. In this review, we will focus on recent findings centered on the transcriptional roles played by ERRα in hepatocytes. Modulation of ERRα activity in both in vitro and in vivo models via genetic or pharmacological manipulation coupled with chromatin-immunoprecipitation (ChIP)-on-chip and ChIP-sequencing (ChIP-seq) studies have been fundamental in delineating the direct roles of ERRα in the control of hepatic gene expression. These studies have identified crucial roles for ERRα in lipid and carbohydrate metabolism as well as in mitochondrial function under both physiological and pathological conditions. The regulation of ERRα expression and activity via ligand-independent modes of action including coregulator binding, post-translational modifications (PTMs) and control of protein stability will be discussed in the context that may serve as valuable tools to modulate ERRα function as new therapeutic avenues for the treatment of hepatic metabolic dysfunction and related diseases.

Keywords:  diabetes; high-fat diet; inflammation; liver cancer; metabolism; non-alcoholic fatty liver disease; nuclear receptor

DOI:  https://doi.org/10.3389/fendo.2019.00206
Proc Natl Acad Sci U S A. 2019 Apr 24. pii: 201814932. [Epub ahead of print]

Cystine-glutamate antiporter xCT deficiency suppresses tumor growth while preserving antitumor immunity.

Michael D Arensman, Xiaoran S Yang, Danielle M Leahy, Lourdes Toral-Barza, Mary Mileski, Edward C Rosfjord, Fang Wang, Shibing Deng, Jeremy S Myers, Robert T Abraham, Christina H Eng.

  T cell-invigorating cancer immunotherapies have near-curative potential. However, their clinical benefit is currently limited, as only a fraction of patients respond, suggesting that these regimens may benefit from combination with tumor-targeting treatments. As oncogenic progression is accompanied by alterations in metabolic pathways, tumors often become heavily reliant on antioxidant machinery and may be susceptible to increases in oxidative stress. The cystine-glutamate antiporter xCT is frequently overexpressed in cancer and fuels the production of the antioxidant glutathione; thus, tumors prone to redox stress may be selectively vulnerable to xCT disruption. However, systemic inhibition of xCT may compromise antitumor immunity, as xCT is implicated in supporting antigen-induced T cell proliferation. Therefore, we utilized immune-competent murine tumor models to investigate whether cancer cell expression of xCT was required for tumor growth in vivo and if deletion of host xCT impacted antitumor immune responses. Deletion of xCT in tumor cells led to defective cystine uptake, accumulation of reactive oxygen species, and impaired tumor growth, supporting a cancer cell-autonomous role for xCT. In contrast, we observed that, although T cell proliferation in culture was exquisitely dependent on xCT expression, xCT was dispensable for T cell proliferation in vivo and for the generation of primary and memory immune responses to tumors. These findings prompted the combination of tumor cell xCT deletion with the immunotherapeutic agent anti-CTLA-4, which dramatically increased the frequency and durability of antitumor responses. Together, these results identify a metabolic vulnerability specific to tumors and demonstrate that xCT disruption can expand the efficacy of anticancer immunotherapies.

Keywords:  T cells; cancer; cystine; immunotherapy; xCT

DOI:  https://doi.org/10.1073/pnas.1814932116
Front Physiol. 2019 ;10 383

Depletion of ATP-Citrate Lyase (ATPCL) Affects Chromosome Integrity Without Altering Histone Acetylation in Drosophila Mitotic Cells.

Patrizia Morciano, Maria Laura Di Giorgio, Antonella Porrazzo, Valerio Licursi, Rodolfo Negri, Yikang Rong, Giovanni Cenci.

  The Citrate Lyase (ACL) is the main cytosolic enzyme that converts the citrate exported from mitochondria by the SLC25A1 carrier in Acetyl Coenzyme A (acetyl-CoA) and oxaloacetate. Acetyl-CoA is a high-energy intermediate common to a large number of metabolic processes including protein acetylation reactions. This renders ACL a key regulator of histone acetylation levels and gene expression in diverse organisms including humans. We have found that depletion of ATPCL, the Drosophila ortholog of human ACL, reduced levels of Acetyl CoA but, unlike its human counterpart, does not affect global histone acetylation and gene expression. Nevertheless, reduced ATPCL levels caused evident, although moderate, mitotic chromosome breakage suggesting that this enzyme plays a partial role in chromosome stability. These defects did not increase upon X-ray irradiation, indicating that they are not dependent on an impairment of DNA repair. Interestingly, depletion of ATPCL drastically increased the frequency of chromosome breaks (CBs) associated to mutations in scheggia, which encodes the ortholog of the mitochondrial citrate carrier SLC25A1 that is also required for chromosome integrity and histone acetylation. Our results indicate that ATPCL has a dispensable role in histone acetylation and prevents massive chromosome fragmentation when citrate efflux is altered.

Keywords:  Drosophila; Drosophila chromosomes; acetyl-CoA; citrate lyase; histone acetylation

DOI:  https://doi.org/10.3389/fphys.2019.00383
Nat Commun. 2019 Apr 23. 10(1): 1841

Metabolic profiling of cancer cells reveals genome-wide crosstalk between transcriptional regulators and metabolism.

Karin Ortmayr, Sébastien Dubuis, Mattia Zampieri.

Transcriptional reprogramming of cellular metabolism is a hallmark of cancer. However, systematic approaches to study the role of transcriptional regulators (TRs) in mediating cancer metabolic rewiring are missing. Here, we chart a genome-scale map of TR-metabolite associations in human cells using a combined computational-experimental framework for large-scale metabolic profiling of adherent cell lines. By integrating intracellular metabolic profiles of 54 cancer cell lines with transcriptomic and proteomic data, we unraveled a large space of associations between TRs and metabolic pathways. We found a global regulatory signature coordinating glucose- and one-carbon metabolism, suggesting that regulation of carbon metabolism in cancer may be more diverse and flexible than previously appreciated. Here, we demonstrate how this TR-metabolite map can serve as a resource to predict TRs potentially responsible for metabolic transformation in patient-derived tumor samples, opening new opportunities in understanding disease etiology, selecting therapeutic treatments and in designing modulators of cancer-related TRs.

DOI: https://doi.org/10.1038/s41467-019-09695-9
Am J Physiol Cell Physiol. 2019 Apr 24.

Autophagy, Apoptosis, and Mitochondria: Molecular Integration and Physiological Relevance in Skeletal Muscle.

Darin Bloemberg, Joe Quadrilatero.

  Apoptosis and autophagy are processes resulting from the integration of cellular stress and death signals. Their individual importance is highlighted by the lethality of various mouse models missing apoptosis or autophagy related genes. In addition to their independent roles, significant overlap exists with respect to the signals which stimulate these processes as well as their effector consequences. While these cellular systems exemplify the programming redundancies which underlie many fundamental biological mechanisms, their intertwined relationship means that dysfunction can promote pathology. Although both autophagy and apoptotic signaling are active in skeletal muscle during various diseases and atrophy, their specific roles here are somewhat unique. Given our growing understanding of how specific changes at the cellular level impact whole-organism physiology, there is an equally growing interest in pharmacological manipulation of apoptosis and/or autophagy for altering human physiology and health.

Keywords:  apoptosis; autophagy; mitochondria; mitophagy; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00261.2018
Annu Rev Nutr. 2019 Apr 24.

Bile Acids as Metabolic Regulators and Nutrient Sensors.

John Y L Chiang, Jessica M Ferrell.

Bile acids facilitate nutrient absorption and are endogenous ligands for nuclear receptors that regulate lipid and energy metabolism. The brain-gut-liver axis plays an essential role in maintaining overall glucose, bile, and immune homeostasis. Fasting and feeding transitions alter nutrient content in the gut, which influences bile acid composition and pool size. In turn, bile acid signaling mediates lipid and glucose use and protection against inflammation. Altered bile acid metabolism resulting from gene mutations, high-fat diets, alcohol, or circadian disruption can contribute to cholestatic and inflammatory diseases, diabetes, and obesity. Bile acids and their derivatives are valuable therapeutic agents for treating these inflammatory metabolic diseases. Expected final online publication date for the Annual Review of Nutrition Volume 39 is August 21, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-nutr-082018-124344
Nat Biomed Eng. 2017 Sep;1(9): 697-713

Multiplexed imaging for diagnosis and therapy.

Kathrin Heinzmann, Lukas M Carter, Jason S Lewis, Eric O Aboagye.

Complex molecular and metabolic phenotypes depict cancers as a constellation of different diseases with common themes. Precision imaging of such phenotypes requires flexible and tunable modalities capable of identifying phenotypic fingerprints by using a restricted number of parameters while ensuring sensitivity to dynamic biological regulation. Common phenotypes can be detected by in vivo imaging technologies, and effectively define the emerging standards for disease classification and patient stratification in radiology. However, for the imaging data to accurately represent a complex fingerprint, the individual imaging parameters need to be measured and analysed in relation to their wider spatial and molecular context. In this respect, targeted palettes of molecular imaging probes facilitate the detection of heterogeneity in oncogene-driven alterations and their response to treatment, and lead to the expansion of rational-design elements for the combination of imaging experiments. In this Review, we evaluate criteria for conducting multiplexed imaging, and discuss its opportunities for improving patient diagnosis and the monitoring of therapy.

DOI: https://doi.org/10.1038/s41551-017-0131-8
Arch Pathol Lab Med. 2019 May;143(5): 643-647

Succinate Dehydrogenase-Deficient Renal Cell Carcinoma.

Tsung-Heng Tsai, Wen-Ying Lee.

Succinate dehydrogenase (SDH)-deficient renal cell carcinoma is a recently recognized distinct subtype of renal cell carcinoma in the 2016 World Health Organization classification. It is associated with SDH gene germline mutations, which also cause paraganglioma/pheochromocytoma, gastrointestinal stromal tumor, and pituitary adenoma. The tumor most commonly presents in young adulthood. The tumors are arranged in solid nests or in tubules and frequently show cystic change. The tumors are composed of cuboidal to oval cells with round nuclei, dispersed chromatin, and inconspicuous nucleoli. The cytoplasm is eosinophilic or flocculent but not truly oncocytic. The most distinctive histologic feature is the presence of cytoplasmic vacuoles or inclusions. Loss of SDH subunit B immunostaining is needed for a definite diagnosis. The prognosis is good for low-grade tumors but worse for tumors with high-grade nuclei, sarcomatoid change, or coagulative necrosis. Long-term follow-up is indicated.

DOI: https://doi.org/10.5858/arpa.2018-0024-RS
Cell Res. 2019 Apr 25.

Vulnerabilities in mIDH2 AML confer sensitivity to APL-like targeted combination therapy.

Vera Mugoni, Riccardo Panella, Giulia Cheloni, Ming Chen, Olga Pozdnyakova, Dina Stroopinsky, Jlenia Guarnerio, Emanuele Monteleone, Jonathan David Lee, Lourdes Mendez, Archita Venugopal Menon, Jon Christopher Aster, Andrew A Lane, Richard Maury Stone, Ilene Galinsky, José Cervera Zamora, Francesco Lo-Coco, Manoj Kumar Bhasin, David Avigan, Letizia Longo, John Gerard Clohessy, Pier Paolo Pandolfi.

Although targeted therapies have proven effective and even curative in human leukaemia, resistance often ensues. IDH enzymes are mutated in ~20% of human AML, with targeted therapies under clinical evaluation. We here characterize leukaemia evolution from mutant IDH2 (mIDH2)-dependence to independence identifying key targetable vulnerabilities of mIDH2 leukaemia that are retained during evolution and progression from early to late stages. Mechanistically, we find that mIDH2 leukaemia are metastable and vulnerable at two distinct levels. On the one hand, they are characterized by oxidative and genotoxic stress, in spite of increased 1-carbon metabolism and glutathione levels. On the other hand, mIDH2 leukaemia display inhibition of LSD1 and a resulting transcriptional signature of all-trans retinoic acid (ATRA) sensitization, in spite of a state of suppressed ATRA signalling due to increased levels of PIN1. We further identify GSH/ROS and PIN1/LSD1 as critical nodes for leukaemia maintenance and the combination of ATRA and arsenic trioxide (ATO) as a key therapeutic modality to target these vulnerabilities. Strikingly, we demonstrate that the combination of ATRA and ATO proves to be a powerfully synergistic and effective therapy in a number of mouse and human mIDH1/2 leukemic models. Thus, our findings pave the way towards the treatment of a sizable fraction of human AMLs through targeted APL-like combinatorial therapies.

DOI: https://doi.org/10.1038/s41422-019-0162-7
Int J Mol Sci. 2019 Apr 19. pii: E1933. [Epub ahead of print]20(8):

The Crosstalk Between Cell Adhesion and Cancer Metabolism.

Bárbara Sousa, Joana Pereira, Joana Paredes.

  Cancer cells preferentially use aerobic glycolysis over mitochondria oxidative phosphorylation for energy production, and this metabolic reprogramming is currently recognized as a hallmark of cancer. Oncogenic signaling frequently converges with this metabolic shift, increasing cancer cells' ability to produce building blocks and energy, as well as to maintain redox homeostasis. Alterations in cell-cell and cell-extracellular matrix (ECM) adhesion promote cancer cell invasion, intravasation, anchorage-independent survival in circulation, and extravasation, as well as homing in a distant organ. Importantly, during this multi-step metastatic process, cells need to induce metabolic rewiring, in order to produce the energy needed, as well as to impair oxidative stress. Although the individual implications of adhesion molecules and metabolic reprogramming in cancer have been widely explored over the years, the crosstalk between cell adhesion molecular machinery and metabolic pathways is far from being clearly understood, in both normal and cancer contexts. This review summarizes our understanding about the influence of cell-cell and cell-matrix adhesion in the metabolic behavior of cancer cells, with a special focus concerning the role of classical cadherins, such as Epithelial (E)-cadherin and Placental (P)-cadherin.

Keywords:  ECM; adhesion; cadherin; cancer; cancer stem cells; metabolism

DOI:  https://doi.org/10.3390/ijms20081933
Sci Rep. 2019 Apr 25. 9(1): 6523

Sensory primary cilium is a responsive cAMP microdomain in renal epithelia.

Rinzhin T Sherpa, Ashraf M Mohieldin, Rajasekharreddy Pala, Dagmar Wachten, Rennolds S Ostrom, Surya M Nauli.

Primary cilia are hair-like cellular extensions that sense microenvironmental signals surrounding cells. The role of adenylyl cyclases in ciliary function has been of interest because the product of adenylyl cyclase activity, cAMP, is relevant to cilia-related diseases. In the present study, we show that vasopressin receptor type-2 (V2R) is localized to cilia in kidney epithelial cells. Pharmacologic inhibition of V2R with tolvaptan increases ciliary length and mechanosensory function. Genetic knockdown of V2R, however, does not have any effect on ciliary length, although the effect of tolvaptan on ciliary length is dampened. Our study reveals that tolvaptan may have a cilia-specific effect independent of V2R or verapamil-sensitive calcium channels. Live-imaging of single cilia shows that V2R activation increases cilioplasmic and cytoplasmic cAMP levels, whereas tolvaptan mediates cAMP changes only in a cilia-specific manner. Furthermore, fluid-shear stress decreases cilioplasmic, but not cytoplasmic cAMP levels. Our data indicate that cilioplasmic and cytoplasmic cAMP levels are differentially modulated. We propose that the cilium is a critical sensor acting as a responsive cAMP microcompartment during physiologically relevant stimuli.

DOI: https://doi.org/10.1038/s41598-019-43002-2
Curr Opin Syst Biol. 2019 Feb;13 59-67

Interrogating metabolism as an electron flow system.

Christian Zerfaß, Munehiro Asally, Orkun S Soyer.

  Metabolism is generally considered as a neatly organised system of modular pathways, shaped by evolution under selection for optimal cellular growth. This view falls short of explaining and predicting a number of key observations about the structure and dynamics of metabolism. We highlight these limitations of a pathway-centric view on metabolism and summarise studies suggesting how these could be overcome by viewing metabolism as a thermodynamically and kinetically constrained, dynamical flow system. Such a systems-level, first-principles based view of metabolism can open up new avenues of metabolic engineering and cures for metabolic diseases and allow better insights to a myriad of physiological processes that are ultimately linked to metabolism. Towards further developing this view, we call for a closer interaction among physical and biological disciplines and an increased use of electrochemical and biophysical approaches to interrogate cellular metabolism together with the microenvironment in which it exists.

Keywords:  Cellular physiology; Cellular trade-offs; Electrobiology; Evolution of metabolism; Metabolic organisation; Redox potential; Thermodynamics

DOI:  https://doi.org/10.1016/j.coisb.2018.10.001
Nat Commun. 2019 Apr 26. 10(1): 1955

A fat-tissue sensor couples growth to oxygen availability by remotely controlling insulin secretion.

Michael J Texada, Anne F Jørgensen, Christian F Christensen, Takashi Koyama, Alina Malita, Daniel K Smith, Dylan F M Marple, E Thomas Danielsen, Sine K Petersen, Jakob L Hansen, Kenneth A Halberg, Kim F Rewitz.

Organisms adapt their metabolism and growth to the availability of nutrients and oxygen, which are essential for development, yet the mechanisms by which this adaptation occurs are not fully understood. Here we describe an RNAi-based body-size screen in Drosophila to identify such mechanisms. Among the strongest hits is the fibroblast growth factor receptor homolog breathless necessary for proper development of the tracheal airway system. Breathless deficiency results in tissue hypoxia, sensed primarily in this context by the fat tissue through HIF-1a prolyl hydroxylase (Hph). The fat relays its hypoxic status through release of one or more HIF-1a-dependent humoral factors that inhibit insulin secretion from the brain, thereby restricting systemic growth. Independently of HIF-1a, Hph is also required for nutrient-dependent Target-of-rapamycin (Tor) activation. Our findings show that the fat tissue acts as the primary sensor of nutrient and oxygen levels, directing adaptation of organismal metabolism and growth to environmental conditions.

DOI: https://doi.org/10.1038/s41467-019-09943-y
Proc Natl Acad Sci U S A. 2019 Apr 26. pii: 201820364. [Epub ahead of print]

Mic60 exhibits a coordinated clustered distribution along and across yeast and mammalian mitochondria.

Stefan Stoldt, Till Stephan, Daniel C Jans, Christian Brüser, Felix Lange, Jan Keller-Findeisen, Dietmar Riedel, Stefan W Hell, Stefan Jakobs.

  Mitochondria are tubular double-membrane organelles essential for eukaryotic life. They form extended networks and exhibit an intricate inner membrane architecture. The MICOS (mitochondrial contact site and cristae organizing system) complex, crucial for proper architecture of the mitochondrial inner membrane, is localized primarily at crista junctions. Harnessing superresolution fluorescence microscopy, we demonstrate that Mic60, a subunit of the MICOS complex, as well as several of its interaction partners are arranged into intricate patterns in human and yeast mitochondria, suggesting an ordered distribution of the crista junctions. We show that Mic60 forms clusters that are preferentially localized in the inner membrane at two opposing sides of the mitochondrial tubules so that they form extended opposing distribution bands. These Mic60 distribution bands can be twisted, resulting in a helical arrangement. Focused ion beam milling-scanning electron microscopy showed that in yeast the twisting of the opposing distribution bands is echoed by the folding of the inner membrane. We show that establishment of the Mic60 distribution bands is largely independent of the cristae morphology. We suggest that Mic60 is part of an extended multiprotein interaction network that scaffolds mitochondria.

Keywords:  FIB-SEM; MICOS; mitochondria; mitoskeleton; nanoscopy

DOI:  https://doi.org/10.1073/pnas.1820364116