bims-camemi 2020-07-19 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2020–07–19
forty-one papers selected by
Christian Frezza, , University of Cambridge, MRC Cancer Unit

PHD3 Loss Promotes Exercise Capacity and Fat Oxidation in Skeletal Muscle.
Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle.
Fasting-mimicking diet and hormone therapy induce breast cancer regression.
Sarcoplasmic Reticulum-Mitochondria Kissing in Cardiomyocytes: Ca2+, ATP, and Undisclosed Secrets.
Mitophagy, Mitochondrial Homeostasis, and Cell Fate.
Mitochondrial Metabolism as a Target for Cancer Therapy.
Cancer cells with defective oxidative phosphorylation require endoplasmic reticulum-to-mitochondria Ca2+ transfer for survival.
Nuclear Factor-Erythroid 2-Related Factor 2 (Nrf2) and Mitochondrial Dynamics/Mitophagy in Neurological Diseases.
The choline transporter Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial function.
Mitochondria-Associated Degradation Pathway (MAD) Function beyond the Outer Membrane.
The Zscan4-Tet2 Transcription Nexus Regulates Metabolic Rewiring and Enhances Proteostasis to Promote Reprogramming.
Myofibroblasts and Fibrosis: Mitochondrial and Metabolic Control of Cellular Differentiation.
Naked mole-rats suppress energy metabolism and modulate membrane cholesterol in chronic hypoxia.
Mitochondrial genome editing: another win for curiosity-driven research.
Mitochondrial dynamics during spermatogenesis.
Structures reveal gatekeeping of the mitochondrial Ca2+ uniporter by MICU1-MICU2.
Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer.
The new role of F1Fo ATP synthase in mitochondria-mediated neurodegeneration and neuroprotection.
Fructose contributes to the Warburg effect for cancer growth.
Tafazzin deficiency impairs CoA-dependent oxidative metabolism in cardiac mitochondria.
Coordinate β-adrenergic inhibition of mitochondrial activity and angiogenesis arrest tumor growth.
Aging shifts mitochondrial dynamics toward fission to promote germline stem cell loss.
Dietary Lipids Induce Ferroptosis in Caenorhabditiselegans and Human Cancer Cells.
DNMT3B deficiency alters mitochondrial biogenesis and α-ketoglutarate levels in human embryonic stem cells.
Mitochondrial Diseases: A Diagnostic Revolution.
Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen.
Mechanism of tumor-suppressive cell competition in flies.
Small Molecule Enhancers of Endosome-to-Cytosol Import Augment Anti-tumor Immunity.
Targeting EMT in Cancer with Repurposed Metabolic Inhibitors.
Effects of dietary iron restriction on kidney mitochondria function and oxidative stress in streptozotocin-diabetic rats.
Phylogenetic analyses with systematic taxon sampling show that mitochondria branch within Alphaproteobacteria.
L1CAM defines the regenerative origin of metastasis-initiating cells in colorectal cancer.
ITLN1 modulates invasive potential and metabolic reprogramming of ovarian cancer cells in omental microenvironment.
Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling.
A redox switch regulates the structure and function of anti-apoptotic BFL-1.
Metabolic engineering generates a transgene-free safety switch for cell therapy.
PRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis.
NOTCH Your Usual Suspect: MYC Charged with Controlling Neuroendocrine Cell-Fate in Small Cell Lung Cancer.
Periodic Oscillations of Myosin-II Mechanically Proofread Cell-Cell Connections to Ensure Robust Formation of the Cardiac Vessel.
Tumors induce de novo steroid biosynthesis in T cells to evade immunity.
Glucose-6-phosphate dehydrogenase is not essential for K-Ras-driven tumor growth or metastasis.

Cell Metab. 2020 Jul 09. pii: S1550-4131(20)30318-1. [Epub ahead of print]

PHD3 Loss Promotes Exercise Capacity and Fat Oxidation in Skeletal Muscle.

Haejin Yoon, Jessica B Spinelli, Elma Zaganjor, Samantha J Wong, Natalie J German, Elizabeth C Randall, Afsah Dean, Allen Clermont, Joao A Paulo, Daniel Garcia, Hao Li, Olivia Rombold, Nathalie Y R Agar, Laurie J Goodyear, Reuben J Shaw, Steven P Gygi, Johan Auwerx, Marcia C Haigis.

  Rapid alterations in cellular metabolism allow tissues to maintain homeostasis during changes in energy availability. The central metabolic regulator acetyl-CoA carboxylase 2 (ACC2) is robustly phosphorylated during cellular energy stress by AMP-activated protein kinase (AMPK) to relieve its suppression of fat oxidation. While ACC2 can also be hydroxylated by prolyl hydroxylase 3 (PHD3), the physiological consequence thereof is poorly understood. We find that ACC2 phosphorylation and hydroxylation occur in an inverse fashion. ACC2 hydroxylation occurs in conditions of high energy and represses fatty acid oxidation. PHD3-null mice demonstrate loss of ACC2 hydroxylation in heart and skeletal muscle and display elevated fatty acid oxidation. Whole body or skeletal muscle-specific PHD3 loss enhances exercise capacity during an endurance exercise challenge. In sum, these data identify an unexpected link between AMPK and PHD3, and a role for PHD3 in acute exercise endurance capacity and skeletal muscle metabolism.

Keywords:  Prolyl hydroxylase 3; acetyl-CoA carboxylase 2 modification; exercise capacity; fat catabolism

DOI:  https://doi.org/10.1016/j.cmet.2020.06.017
Cell Res. 2020 Jul 15.

Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle.

Jing Liu, Yunhua Peng, Le Shi, Lixin Wan, Hiroyuki Inuzuka, Jiangang Long, Jianping Guo, Jinfang Zhang, Min Yuan, Shuangxi Zhang, Xun Wang, Jing Gao, Xiangpeng Dai, Shozo Furumoto, Lijun Jia, Pier Paolo Pandolfi, John M Asara, William G Kaelin, Jiankang Liu, Wenyi Wei.

Whether glucose is predominantly metabolized via oxidative phosphorylation or glycolysis differs between quiescent versus proliferating cells, including tumor cells. However, how glucose metabolism is coordinated with cell cycle in mammalian cells remains elusive. Here, we report that mammalian cells predominantly utilize the tricarboxylic acid (TCA) cycle in G1 phase, but prefer glycolysis in S phase. Mechanistically, coupling cell cycle with metabolism is largely achieved by timely destruction of IDH1/2, key TCA cycle enzymes, in a Skp2-dependent manner. As such, depleting SKP2 abolishes cell cycle-dependent fluctuation of IDH1 protein abundance, leading to reduced glycolysis in S phase. Furthermore, elevated Skp2 abundance in prostate cancer cells destabilizes IDH1 to favor glycolysis and subsequent tumorigenesis. Therefore, our study reveals a mechanistic link between two cancer hallmarks, aberrant cell cycle and addiction to glycolysis, and provides the underlying mechanism for the coupling of metabolic fluctuation with periodic cell cycle in mammalian cells.

DOI: https://doi.org/10.1038/s41422-020-0372-z
Nature. 2020 Jul 15.

Fasting-mimicking diet and hormone therapy induce breast cancer regression.

Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Min Wei, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Lorenzo Ferrando, Francesco Piacente, Alberto Tagliafico, Michele Cilli, Luca Mastracci, Valerio G Vellone, Silvano Piazza, Anna Laura Cremonini, Raffaella Gradaschi, Carolina Mantero, Mario Passalacqua, Alberto Ballestrero, Gabriele Zoppoli, Michele Cea, Annalisa Arrighi, Patrizio Odetti, Fiammetta Monacelli, Giulia Salvadori, Salvatore Cortellino, Hans Clevers, Filippo De Braud, Samir G Sukkar, Alessandro Provenzani, Valter D Longo, Alessio Nencioni.

Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.

DOI: https://doi.org/10.1038/s41586-020-2502-7
Front Cell Dev Biol. 2020 ;8 532

Sarcoplasmic Reticulum-Mitochondria Kissing in Cardiomyocytes: Ca2+, ATP, and Undisclosed Secrets.

Michela Rossini, Riccardo Filadi.

  In cardiomyocytes, to carry out cell contraction, the distribution, morphology, and dynamic interaction of different cellular organelles are tightly regulated. For instance, the repetitive close apposition between junctional sarcoplasmic reticulum (jSR) and specialized sarcolemma invaginations, called transverse-tubules (TTs), is essential for an efficient excitation-contraction coupling (ECC). Upon an action potential, Ca2+ microdomains, generated in synchrony at the interface between TTs and jSR, underlie the prompt increase in cytosolic Ca2+ concentration, ultimately responsible for cell contraction during systole. This process requires a considerable amount of energy and the active participation of mitochondria, which encompass ∼30% of the cell volume and represent the major source of ATP in the heart. Importantly, in adult cardiomyocytes, mitochondria are distributed in a highly orderly fashion and strategically juxtaposed with SR. By taking advantage of the vicinity to Ca2+ releasing sites, they take up Ca2+ and modulate ATP synthesis according to the specific cardiac workload. Interestingly, with respect to SR, a biased, polarized positioning of mitochondrial Ca2+ uptake/efflux machineries has been reported, hinting the importance of a strictly regulated mitochondrial Ca2+ handling for heart activity. This notion, however, has been questioned by the observation that, in some mouse models, the deficiency of specific molecules, modulating mitochondrial Ca2+ dynamics, triggers non-obvious cardiac phenotypes. This review will briefly summarize the physiological significance of SR-mitochondria apposition in cardiomyocytes, as well as the pathological consequences of an altered organelle communication, focusing on Ca2+ signaling. We will discuss ongoing debates and propose future research directions.

Keywords:  ATP; Ca2+; MCU; cardiomyocyte; heart; mitochondria; organelle contacts; sarcoplasmic reticulum

DOI:  https://doi.org/10.3389/fcell.2020.00532
Front Cell Dev Biol. 2020 ;8 467

Mitophagy, Mitochondrial Homeostasis, and Cell Fate.

Kaili Ma, Guo Chen, Wenhui Li, Oliver Kepp, Yushan Zhu, Quan Chen.

  Mitochondria are highly plastic and dynamic organelles that have graded responses to the changing cellular, environmental, and developmental cues. Mitochondria undergo constant mitochondrial fission and fusion, mitochondrial biogenesis, and mitophagy, which coordinately control mitochondrial morphology, quantity, quality, turnover, and inheritance. Mitophagy is a cellular process that selectively removes the aged and damaged mitochondria via the specific sequestration and engulfment of mitochondria for subsequent lysosomal degradation. It plays a pivotal role in reinstating cellular homeostasis in normal physiology and conditions of stress. Damaged mitochondria may either instigate innate immunity through the overproduction of ROS or the release of mtDNA, or trigger cell death through the release of cytochrome c and other apoptogenic factors when mitochondria damage is beyond repair. Distinct molecular machineries and signaling pathways are found to regulate these mitochondrial dynamics and behaviors. It is less clear how mitochondrial behaviors are coordinated at molecular levels. BCL2 family proteins interact within family members to regulate mitochondrial outer membrane permeabilization and apoptosis. They were also described as global regulators of mitochondrial homeostasis and mitochondrial fate through their interaction with distinct partners including Drp1, mitofusins, PGAM5, and even LC3 that involved mitochondrial dynamics and behaviors. In this review, we summarize recent findings on molecular pathways governing mitophagy and its coordination with other mitochondrial behaviors, which together determine cellular fate.

Keywords:  cell fate; mitochondrial apoptosis; mitochondrial dynamics; mitophagy; mitophagy receptors

DOI:  https://doi.org/10.3389/fcell.2020.00467
Cell Metab. 2020 Jul 08. pii: S1550-4131(20)30320-X. [Epub ahead of print]

Mitochondrial Metabolism as a Target for Cancer Therapy.

Karthik Vasan, Marie Werner, Navdeep S Chandel.

  Recent evidence in humans and mice supports the notion that mitochondrial metabolism is active and necessary for tumor growth. Mitochondrial metabolism supports tumor anabolism by providing key metabolites for macromolecule synthesis and generating oncometabolites to maintain the cancer phenotype. Moreover, there are multiple clinical trials testing the efficacy of inhibiting mitochondrial metabolism as a new cancer therapeutic treatment. In this review, we discuss the rationale of using these anti-cancer agents in clinical trials and highlight how to effectively utilize them in different tumor contexts.

Keywords:  metformin; mitochondria

DOI:  https://doi.org/10.1016/j.cmet.2020.06.019
Sci Signal. 2020 Jul 14. pii: eaay1212. [Epub ahead of print]13(640):

Cancer cells with defective oxidative phosphorylation require endoplasmic reticulum-to-mitochondria Ca2+ transfer for survival.

Cesar Cardenas, Alenka Lovy, Eduardo Silva-Pavez, Felix Urra, Craig Mizzoni, Ulises Ahumada-Castro, Galdo Bustos, Fabian Jaňa, Pablo Cruz, Paula Farias, Elizabeth Mendoza, Hernan Huerta, Paola Murgas, Martin Hunter, Melany Rios, Oscar Cerda, Irene Georgakoudi, Armen Zakarian, Jordi Molgó, J Kevin Foskett.

Spontaneous Ca2+ signaling from the InsP3R intracellular Ca2+ release channel to mitochondria is essential for optimal oxidative phosphorylation (OXPHOS) and ATP production. In cells with defective OXPHOS, reductive carboxylation replaces oxidative metabolism to maintain amounts of reducing equivalents and metabolic precursors. To investigate the role of mitochondrial Ca2+ uptake in regulating bioenergetics in these cells, we used OXPHOS-competent and OXPHOS-defective cells. Inhibition of InsP3R activity or mitochondrial Ca2+ uptake increased α-ketoglutarate (αKG) abundance and the NAD+/NADH ratio, indicating that constitutive endoplasmic reticulum (ER)-to-mitochondria Ca2+ transfer promoted optimal αKG dehydrogenase (αKGDH) activity. Reducing mitochondrial Ca2+ inhibited αKGDH activity and increased NAD+, which induced SIRT1-dependent autophagy in both OXPHOS-competent and OXPHOS-defective cells. Whereas autophagic flux in OXPHOS-competent cells promoted cell survival, it was impaired in OXPHOS-defective cells because of inhibition of autophagosome-lysosome fusion. Inhibition of αKGDH and impaired autophagic flux in OXPHOS-defective cells resulted in pronounced cell death in response to interruption of constitutive flux of Ca2+ from ER to mitochondria. These results demonstrate that mitochondria play a fundamental role in maintaining bioenergetic homeostasis of both OXPHOS-competent and OXPHOS-defective cells, with Ca2+ regulation of αKGDH activity playing a pivotal role. Inhibition of ER-to-mitochondria Ca2+ transfer may represent a general therapeutic strategy against cancer cells regardless of their OXPHOS status.

DOI: https://doi.org/10.1126/scisignal.aay1212
Antioxidants (Basel). 2020 Jul 15. pii: E617. [Epub ahead of print]9(7):

Nuclear Factor-Erythroid 2-Related Factor 2 (Nrf2) and Mitochondrial Dynamics/Mitophagy in Neurological Diseases.

Tae-Cheon Kang.

  Mitochondria play an essential role in bioenergetics and respiratory functions for cell viability through numerous biochemical processes. To maintain mitochondria quality control and homeostasis, mitochondrial morphologies change rapidly in response to external insults and changes in metabolic status through fusion and fission (so called mitochondrial dynamics). Furthermore, damaged mitochondria are removed via a selective autophagosomal process, referred to as mitophagy. Although mitochondria are one of the sources of reactive oxygen species (ROS), they are themselves vulnerable to oxidative stress. Thus, endogenous antioxidant defense systems play an important role in cell survival under physiological and pathological conditions. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that maintains redox homeostasis by regulating antioxidant-response element (ARE)-dependent transcription and the expression of antioxidant defense enzymes. Although the Nrf2 system is positively associated with mitochondrial biogenesis and mitochondrial quality control, the relationship between Nrf2 signaling and mitochondrial dynamics/mitophagy has not been sufficiently addressed in the literature. This review article describes recent clinical and experimental observations on the relationship between Nrf2 and mitochondrial dynamics/mitophagy in various neurological diseases.

Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; cerebrovascular disease; epilepsy; mitochondrial fission; mitochondrial fusion

DOI:  https://doi.org/10.3390/antiox9070617
Nat Commun. 2020 Jul 13. 11(1): 3479

The choline transporter Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial function.

J Allen Bennett, Michael A Mastrangelo, Sara K Ture, Charles O Smith, Shannon G Loelius, Rachel A Berg, Xu Shi, Ryan M Burke, Sherry L Spinelli, Scott J Cameron, Thomas E Carey, Paul S Brookes, Robert E Gerszten, Maria Sabater-Lleal, Paul S de Vries, Jennifer E Huffman, Nicholas L Smith, Craig N Morrell, Charles J Lowenstein.

Genetic factors contribute to the risk of thrombotic diseases. Recent genome wide association studies have identified genetic loci including SLC44A2 which may regulate thrombosis. Here we show that Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial energetics. We find that Slc44a2 null mice (Slc44a2(KO)) have increased bleeding times and delayed thrombosis compared to wild-type (Slc44a2(WT)) controls. Platelets from Slc44a2(KO) mice have impaired activation in response to thrombin. We discover that Slc44a2 mediates choline transport into mitochondria, where choline metabolism leads to an increase in mitochondrial oxygen consumption and ATP production. Platelets lacking Slc44a2 contain less ATP at rest, release less ATP when activated, and have an activation defect that can be rescued by exogenous ADP. Taken together, our data suggest that mitochondria require choline for maximum function, demonstrate the importance of mitochondrial metabolism to platelet activation, and reveal a mechanism by which Slc44a2 influences thrombosis.

DOI: https://doi.org/10.1038/s41467-020-17254-w
Cell Rep. 2020 Jul 14. pii: S2211-1247(20)30883-4. [Epub ahead of print]32(2): 107902

Mitochondria-Associated Degradation Pathway (MAD) Function beyond the Outer Membrane.

Pin-Chao Liao, Dana M Alessi Wolken, Edith Serrano, Pallavi Srivastava, Liza A Pon.

  The mitochondria-associated degradation pathway (MAD) mediates ubiquitination and degradation of mitochondrial outer membrane (MOM) proteins by the proteasome. We find that the MAD, but not other quality-control pathways including macroautophagy, mitophagy, or mitochondrial chaperones and proteases, is critical for yeast cellular fitness under conditions of paraquat (PQ)-induced oxidative stress in mitochondria. Specifically, inhibition of the MAD increases PQ-induced defects in growth and mitochondrial quality and decreases chronological lifespan. We use mass spectrometry analysis to identify possible MAD substrates as mitochondrial proteins that exhibit increased ubiquitination in response to PQ treatment and inhibition of the MAD. We identify candidate substrates in the mitochondrial matrix and inner membrane and confirm that two matrix proteins are MAD substrates. Our studies reveal a broader function for the MAD in mitochondrial protein surveillance beyond the MOM and a major role for the MAD in cellular and mitochondrial fitness in response to chronic, low-level oxidative stress in mitochondria.

Keywords:  Saccharomyces cerevisiae; chronological lifespan; mitochondrial quality control; mitophagy; oxidative stress; paraquat; proteasome; proteostasis; reactive oxygen species; ubiquitin

DOI:  https://doi.org/10.1016/j.celrep.2020.107902
Cell Rep. 2020 Jul 14. pii: S2211-1247(20)30858-5. [Epub ahead of print]32(2): 107877

The Zscan4-Tet2 Transcription Nexus Regulates Metabolic Rewiring and Enhances Proteostasis to Promote Reprogramming.

Zhou-Li Cheng, Meng-Li Zhang, Huai-Peng Lin, Chao Gao, Jun-Bin Song, Zhihong Zheng, Linpeng Li, Yanan Zhang, Xiaoqi Shen, Hao Zhang, Zhenghui Huang, Wuqiang Zhan, Cheng Zhang, Xu Hu, Yi-Ping Sun, Lubing Jiang, Lei Sun, Yanhui Xu, Chen Yang, Yuanlong Ge, Yong Zhao, Xingguo Liu, Hui Yang, Pengyuan Liu, Xing Guo, Kun-Liang Guan, Yue Xiong, Mingliang Zhang, Dan Ye.

  Evolutionarily conserved SCAN (named after SRE-ZBP, CTfin51, AW-1, and Number 18 cDNA)-domain-containing zinc finger transcription factors (ZSCAN) have been found in both mouse and human genomes. Zscan4 is transiently expressed during zygotic genome activation (ZGA) in preimplantation embryos and induced pluripotent stem cell (iPSC) reprogramming. However, little is known about the mechanism of Zscan4 underlying these processes of cell fate control. Here, we show that Zscan4f, a representative of ZSCAN proteins, is able to recruit Tet2 through its SCAN domain. The Zscan4f-Tet2 interaction promotes DNA demethylation and regulates the expression of target genes, particularly those encoding glycolytic enzymes and proteasome subunits. Zscan4f regulates metabolic rewiring, enhances proteasome function, and ultimately promotes iPSC generation. These results identify Zscan4f as an important partner of Tet2 in regulating target genes and promoting iPSC generation and suggest a possible and common mechanism shared by SCAN family transcription factors to recruit ten-eleven translocation (TET) DNA dioxygenases to regulate diverse cellular processes, including reprogramming.

Keywords:  SCAN domain; TET2; ZSCAN4; iPSCs; induced pluripotent stem cells; metabolic rewiring; proteasome function; stem cell potency

DOI:  https://doi.org/10.1016/j.celrep.2020.107877
Circ Res. 2020 Jul 17. 127(3): 427-447

Myofibroblasts and Fibrosis: Mitochondrial and Metabolic Control of Cellular Differentiation.

Andrew A Gibb, Michael P Lazaropoulos, John W Elrod.

  Cardiac fibrosis is mediated by the activation of resident cardiac fibroblasts, which differentiate into myofibroblasts in response to injury or stress. Although myofibroblast formation is a physiological response to acute injury, such as myocardial infarction, myofibroblast persistence, as occurs in heart failure, contributes to maladaptive remodeling and progressive functional decline. Although traditional pathways of activation, such as TGFβ (transforming growth factor β) and AngII (angiotensin II), have been well characterized, less understood are the alterations in mitochondrial function and cellular metabolism that are necessary to initiate and sustain myofibroblast formation and function. In this review, we highlight recent reports detailing the mitochondrial and metabolic mechanisms that contribute to myofibroblast differentiation, persistence, and function with the hope of identifying novel therapeutic targets to treat, and potentially reverse, tissue organ fibrosis.

Keywords:  fibrosis; heart failure; metabolism; mitochondria; myofibroblast

DOI:  https://doi.org/10.1161/CIRCRESAHA.120.316958
Am J Physiol Regul Integr Comp Physiol. 2020 Aug 01. 319(2): R148-R155

Naked mole-rats suppress energy metabolism and modulate membrane cholesterol in chronic hypoxia.

Elie Farhat, Maiah E M Devereaux, Matthew E Pamenter, Jean-Michel Weber.

  Naked mole-rats (NMRs) are mammalian champions of hypoxia tolerance that enter metabolic suppression to survive in low oxygen environments. Common physiological mechanisms used by animals to suppress metabolic rate include downregulating energy metabolism (ATP supply) as well as ion pumps (primary cellular ATP consumers). A recent goldfish study demonstrated that remodeling of membrane lipids may mediate these responses, but it is unknown if NMR employs the same strategies; therefore, we aimed to test the hypotheses that these fossorial mammals 1) downregulate the activity of key enzymes of glycolysis, tricarboxylic acid (TCA) cycle, and β-oxidation, 2) inhibit sodium-potassium-ATPase, and 3) alter membrane lipids in response to chronic hypoxia. We found that NMRs exposed to 11% oxygen for 4 wk had a lower metabolic rate by 34%. This suppression occurs concurrently with tissue-specific 25-99% decreases in metabolic enzymes activities, a 77% decrease in brain sodium/potassium-ATPase activity, and widespread changes in membrane cholesterol abundance. By reducing glycolytic and β-oxidation fluxes, NMRs decrease the supply of acetyl-CoA to the TCA cycle. By contrast, there is a 94% upregulation of citrate synthase in the heart, possibly to support circulation and thus oxygen supply to other organs. Taken together, these responses may reflect a coordinated physiological response to hypoxia, but a clear functional link between changes in membrane composition and enzyme activities could not be established. Nevertheless, this is the first demonstration that hypometabolic NMRs alter the lipid composition of their membranes in response to chronic in vivo exposure to hypoxia.

Keywords:  enzymes; hypoxia tolerance; membrane lipids; metabolic suppression; sodium/potassium ATPase

DOI:  https://doi.org/10.1152/ajpregu.00057.2020
Nature. 2020 Jul;583(7816): 332

Mitochondrial genome editing: another win for curiosity-driven research.



Keywords:  Biological techniques; CRISPR-Cas9 genome editing; Genetics; Metabolism

DOI:  https://doi.org/10.1038/d41586-020-02094-x
J Cell Sci. 2020 Jul 16. pii: jcs235937. [Epub ahead of print]133(14):

Mitochondrial dynamics during spermatogenesis.

Grigor Varuzhanyan, David C Chan.

  Mitochondrial fusion and fission (mitochondrial dynamics) are homeostatic processes that safeguard normal cellular function. This relationship is especially strong in tissues with constitutively high energy demands, such as brain, heart and skeletal muscle. Less is known about the role of mitochondrial dynamics in developmental systems that involve changes in metabolic function. One such system is spermatogenesis. The first mitochondrial dynamics gene, Fuzzy onions (Fzo), was discovered in 1997 to mediate mitochondrial fusion during Drosophila spermatogenesis. In mammals, however, the role of mitochondrial fusion during spermatogenesis remained unknown for nearly two decades after discovery of Fzo Mammalian spermatogenesis is one of the most complex and lengthy differentiation processes in biology, transforming spermatogonial stem cells into highly specialized sperm cells over a 5-week period. This elaborate differentiation process requires several developmentally regulated mitochondrial and metabolic transitions, making it an attractive model system for studying mitochondrial dynamics in vivo We review the emerging role of mitochondrial biology, and especially its dynamics, during the development of the male germ line.

Keywords:  Membrane fission; Membrane fusion; Mitochondrial dynamics; Spermatogenesis

DOI:  https://doi.org/10.1242/jcs.235937
Elife. 2020 Jul 15. pii: e59991. [Epub ahead of print]9

Structures reveal gatekeeping of the mitochondrial Ca2+ uniporter by MICU1-MICU2.

Chongyuan Wang, Agata Jacewicz, Bryce D Delgado, Rozbeh Baradaran, Stephen Barstow Long.

  The mitochondrial calcium uniporter is a Ca2+-gated ion channel complex that controls mitochondrial Ca2+ entry and regulates cell metabolism. MCU and EMRE form the channel while Ca2+-dependent regulation is conferred by MICU1 and MICU2 through an enigmatic process. We present a cryo-EM structure of an MCU-EMRE-MICU1-MICU2 holocomplex comprising MCU and EMRE subunits from the beetle Tribolium castaneum in complex with a human MICU1-MICU2 heterodimer at 3.3 Å resolution. With analogy to how neuronal channels are blocked by protein toxins, a uniporter interaction domain on MICU1 binds to a channel receptor site comprising MCU and EMRE subunits to inhibit ion flow under resting Ca2+ conditions. A Ca2+-bound structure of MICU1-MICU2 at 3.1 Å resolution indicates how Ca2+-dependent changes enable dynamic response to cytosolic Ca2+ signals.

Keywords:  biochemistry; chemical biology; human; molecular biophysics; structural biology

DOI:  https://doi.org/10.7554/eLife.59991
Cancer Cell. 2020 Jun 23. pii: S1535-6108(20)30309-3. [Epub ahead of print]

Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance in Prostate Cancer.

Zeda Zhang, Wouter R Karthaus, Young Sun Lee, Vianne R Gao, Chao Wu, Joshua W Russo, Menghan Liu, Jose Mauricio Mota, Wassim Abida, Eliot Linton, Eugine Lee, Spencer D Barnes, Hsuan-An Chen, Ninghui Mao, John Wongvipat, Danielle Choi, Xiaoping Chen, Huiyong Zhao, Katia Manova-Todorova, Elisa de Stanchina, Mary-Ellen Taplin, Steven P Balk, Dana E Rathkopf, Anuradha Gopalan, Brett S Carver, Ping Mu, Xuejun Jiang, Philip A Watson, Charles L Sawyers.

  Despite the development of second-generation antiandrogens, acquired resistance to hormone therapy remains a major challenge in treating advanced prostate cancer. We find that cancer-associated fibroblasts (CAFs) can promote antiandrogen resistance in mouse models and in prostate organoid cultures. We identify neuregulin 1 (NRG1) in CAF supernatant, which promotes resistance in tumor cells through activation of HER3. Pharmacological blockade of the NRG1/HER3 axis using clinical-grade blocking antibodies re-sensitizes tumors to hormone deprivation in vitro and in vivo. Furthermore, patients with castration-resistant prostate cancer with increased tumor NRG1 activity have an inferior response to second-generation antiandrogen therapy. This work reveals a paracrine mechanism of antiandrogen resistance in prostate cancer amenable to clinical testing using available targeted therapies.

Keywords:  NRG1/neuregulin 1; cancer-associated fibroblast; drug resistance; hormone therapy; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2020.06.005
Exp Neurol. 2020 Jul 09. pii: S0014-4886(20)30231-4. [Epub ahead of print] 113400

The new role of F1Fo ATP synthase in mitochondria-mediated neurodegeneration and neuroprotection.

Nelli Mnatsakanyan, Elizabeth Ann Jonas.

  The mitochondrial F1Fo ATP synthase is one of the most abundant proteins of the mitochondrial inner membrane, which catalyzes the final step of oxidative phosphorylation to synthesize ATP from ADP and Pi. ATP synthase uses the electrochemical gradient of protons (ΔμH+) across the mitochondrial inner membrane to synthesize ATP. Under certain pathophysiological conditions, ATP synthase can run in reverse to hydrolyze ATP and build the necessary ΔμH+ across the mitochondrial inner membrane. Tight coupling between these two processes, proton translocation and ATP synthesis, is achieved by the unique rotational mechanism of ATP synthase and is necessary for efficient cellular metabolism and cell survival. The uncoupling of these processes, dissipation of mitochondrial inner membrane potential, elevated levels of ROS, low matrix content of ATP in combination with other cellular malfunction trigger the opening of the mitochondrial permeability transition pore in the mitochondrial inner membrane. In this review we will discuss the new role of ATP synthase beyond oxidative phosphorylation. We will highlight its function as a unique regulator of cell life and death and as a key target in mitochondria-mediated neurodegeneration and neuroprotection.

Keywords:  ATP synthase; Mitochondrial permeability transition pore; Neurodegeneration; Neuroprotection

DOI:  https://doi.org/10.1016/j.expneurol.2020.113400
Cancer Metab. 2020 ;8 16

Fructose contributes to the Warburg effect for cancer growth.

Takahiko Nakagawa, Miguel A Lanaspa, Inigo San Millan, Mehdi Fini, Christopher J Rivard, Laura G Sanchez-Lozada, Ana Andres-Hernando, Dean R Tolan, Richard J Johnson.

  Obesity and metabolic syndrome are strongly associated with cancer, and these disorders may share a common mechanism. Recently, fructose has emerged as a driving force to develop obesity and metabolic syndrome. Thus, we assume that fructose may be the mechanism to explain why obesity and metabolic syndrome are linked with cancer. Clinical and experimental evidence showed that fructose intake was associated with cancer growth and that fructose transporters are upregulated in various malignant tumors. Interestingly, fructose metabolism can be driven under low oxygen conditions, accelerates glucose utilization, and exhibits distinct effects as compared to glucose, including production of uric acid and lactate as major byproducts. Fructose promotes the Warburg effect to preferentially downregulate mitochondrial respiration and increases aerobic glycolysis that may aid metastases that initially have low oxygen supply. In the process, uric acid may facilitate carcinogenesis by inhibiting the TCA cycle, stimulating cell proliferation by mitochondrial ROS, and blocking fatty acid oxidation. Lactate may also contribute to cancer growth by suppressing fat oxidation and inducing oncogene expression. The ability of fructose metabolism to directly stimulate the glycolytic pathway may have been protective for animals living with limited access to oxygen, but may be deleterious toward stimulating cancer growth and metastasis for humans in modern society. Blocking fructose metabolism may be a novel approach for the prevention and treatment of cancer.

Keywords:  Cancer; Fructose; Hypoxia; Lactate; Mitochondria; Polyol pathway; Uric acid

DOI:  https://doi.org/10.1186/s40170-020-00222-9
J Biol Chem. 2020 Jul 14. pii: jbc.RA119.011229. [Epub ahead of print]

Tafazzin deficiency impairs CoA-dependent oxidative metabolism in cardiac mitochondria.

Catherine H Le, Lindsay G Benage, Kalyn S Specht, Lance C Li Puma, Christopher M Mulligan, Adam L Heuberger, Jessica E Prenni, Steven M Claypool, Kathryn C Chatfield, Genevieve C Sparagna, Adam J Chicco.

  Barth syndrome (BTHS) is a mitochondrial myopathy resulting from mutations in the tafazzin (TAZ) gene encoding a phospholipid transacylase required for cardiolipin remodeling. Cardiolipin is phospholipid of the inner mitochondrial membrane essential for the function of numerous mitochondrial proteins and processes. However, it is unclear how tafazzin deficiency impacts cardiac mitochondrial metabolism. To address this question while avoiding confounding effects of cardiomyopathy on mitochondrial phenotype, we utilized Taz-shRNA "knockdown" (TazKD ) mice, which exhibit defective cardiolipin remodeling and respiratory supercomplex instability characteristic of human BTHS, but normal cardiac function into adulthood. Consistent with previous reports from other models, mitochondrial H2O2 emission and oxidative damage were greater in TazKD than in wild-type (WT) hearts, but there were no differences in oxidative phosphorylation coupling efficiency or membrane potential. Fatty acid and pyruvate oxidation capacities were 40-60% lower in TazKD mitochondria, but an upregulation of glutamate oxidation supported respiration rates approximating those with pyruvate and palmitoylcarnitine in WT. Deficiencies in mitochondrial CoA and shifts in the cardiac acyl-CoA profile paralleled changes in fatty acid oxidation enzymes and acyl-CoA thioesterases suggesting limitations of CoA availability or "trapping" in TazKD mitochondrial metabolism. Incubation of TazKD mitochondria with exogenous CoA partially rescued pyruvate and palmitoylcarnitine oxidation capacities, implicating dysregulation of CoA-dependent intermediary metabolism rather than respiratory chain defects in the bioenergetic impacts of tafazzin-deficiency. These findings support links among cardiolipin abnormalities, respiratory supercomplex instability and mitochondrial oxidant production, and shed new light on the distinct metabolic consequences of tafazzin-deficiency in the mammalian heart.

Keywords:  Barth Syndrome (BTHS); X-linked mitochondrial disorder; bioenergetics; cardiolipin; cardioskeletal myopathy; lipid metabolism; mitochondrial disease; mitochondrial metabolism; phospholipid transacylase; tafazzin (TAZ)

DOI:  https://doi.org/10.1074/jbc.RA119.011229
Nat Commun. 2020 Jul 17. 11(1): 3606

Coordinate β-adrenergic inhibition of mitochondrial activity and angiogenesis arrest tumor growth.

Cristina Nuevo-Tapioles, Fulvio Santacatterina, Konstantinos Stamatakis, Cristina Núñez de Arenas, Marta Gómez de Cedrón, Laura Formentini, José M Cuezva.

Mitochondrial metabolism has emerged as a promising target against the mechanisms of tumor growth. Herein, we have screened an FDA-approved library to identify drugs that inhibit mitochondrial respiration. The β1-blocker nebivolol specifically hinders oxidative phosphorylation in cancer cells by concertedly inhibiting Complex I and ATP synthase activities. Complex I inhibition is mediated by interfering the phosphorylation of NDUFS7. Inhibition of the ATP synthase is exerted by the overexpression and binding of the ATPase Inhibitory Factor 1 (IF1) to the enzyme. Remarkably, nebivolol also arrests tumor angiogenesis by arresting endothelial cell proliferation. Altogether, targeting mitochondria and angiogenesis triggers a metabolic and oxidative stress crisis that restricts the growth of colon and breast carcinomas. Nebivolol holds great promise to be repurposed for the treatment of cancer patients.

DOI: https://doi.org/10.1038/s41467-020-17384-1
Aging Cell. 2020 Jul 14. e13191

Aging shifts mitochondrial dynamics toward fission to promote germline stem cell loss.

Oyundari Amartuvshin, Chi-Hung Lin, Shao-Chun Hsu, Shih-Han Kao, Alvin Chen, Wei-Chun Tang, Han-Lin Chou, Dong-Lin Chang, Yen-Yang Hsu, Bai-Shiou Hsiao, Elham Rastegari, Kun-Yang Lin, Yu-Ting Wang, Chi-Kuang Yao, Guang-Chao Chen, Bi-Chang Chen, Hwei-Jan Hsu.

  Changes in mitochondrial dynamics (fusion and fission) are known to occur during stem cell differentiation; however, the role of this phenomenon in tissue aging remains unclear. Here, we report that mitochondrial dynamics are shifted toward fission during aging of Drosophila ovarian germline stem cells (GSCs), and this shift contributes to aging-related GSC loss. We found that as GSCs age, mitochondrial fragmentation and expression of the mitochondrial fission regulator, Dynamin-related protein (Drp1), are both increased, while mitochondrial membrane potential is reduced. Moreover, preventing mitochondrial fusion in GSCs results in highly fragmented depolarized mitochondria, decreased BMP stemness signaling, impaired fatty acid metabolism, and GSC loss. Conversely, forcing mitochondrial elongation promotes GSC attachment to the niche. Importantly, maintenance of aging GSCs can be enhanced by suppressing Drp1 expression to prevent mitochondrial fission or treating with rapamycin, which is known to promote autophagy via TOR inhibition. Overall, our results show that mitochondrial dynamics are altered during physiological aging, affecting stem cell homeostasis via coordinated changes in stemness signaling, niche contact, and cellular metabolism. Such effects may also be highly relevant to other stem cell types and aging-induced tissue degeneration.

Keywords:  BMP; Drp1; GSC; Marf; mitochondrial fission; mitochondrial fusion

DOI:  https://doi.org/10.1111/acel.13191
Dev Cell. 2020 Jun 30. pii: S1534-5807(20)30498-6. [Epub ahead of print]

Dietary Lipids Induce Ferroptosis in Caenorhabditiselegans and Human Cancer Cells.

Marcos A Perez, Leslie Magtanong, Scott J Dixon, Jennifer L Watts.

  Dietary lipids impact development, homeostasis, and disease, but links between specific dietary fats and cell fates are poorly understood. Ferroptosis is an iron-dependent form of nonapoptotic cell death associated with oxidized polyunsaturated phospholipids. Here, we show that dietary ingestion of the polyunsaturated fatty acid (PUFA) dihomogamma-linolenic acid (DGLA; 20:3n-6) can trigger germ-cell ferroptosis and sterility in the nematode Caenorhabditis elegans. Exogenous DGLA is also sufficient to induce ferroptosis in human cells, pinpointing this omega-6 PUFA as a conserved metabolic instigator of this lethal process. In both C. elegans and human cancer cells, ether-lipid synthesis protects against ferroptosis. These results establish C. elegans as a powerful animal model to study the induction and modulation of ferroptosis by dietary fats and indicate that endogenous ether lipids act to prevent this nonapoptotic cell fate.

Keywords:  ferroptosis; germ cells; polyunsaturated fatty acids

DOI:  https://doi.org/10.1016/j.devcel.2020.06.019
Stem Cells. 2020 Jul 11.

DNMT3B deficiency alters mitochondrial biogenesis and α-ketoglutarate levels in human embryonic stem cells.

Artur Cieslar-Pobuda, Theresa D Ahrens, Safak Caglayan, Sidney Behringer, Luciana Hannibal, Judith Staerk.

Embryonic stem cell (ESC) renewal and differentiation is regulated by metabolites that serve as co-factors for epigenetic enzymes. Increase of α-ketoglutarate (α-KG), a co-factor for histone and DNA demethylases, triggers multi-lineage differentiation in human ESCs. To gain further insight how the metabolic fluxes in pluripotent stem cells can be influenced by inactivating mutations in epigenetic enzymes, we generated human ESCs deficient for de novo DNA methyltransferases (DNMT) 3A and 3B. Our data reveal a bidirectional dependence between DNMT3B and α-KG levels: a-KG is significantly upregulated in cells deficient for DNMT3B, while DNMT3B expression is downregulated in human ESCs treated with α-KG. In addition, DNMT3B null human ESCs exhibit a disturbed mitochondrial fission and fusion balance and a switch from glycolysis to oxidative phosphorylation. Taken together, our data reveal a novel link between DNMT3B and the metabolic flux of human ESCs. © AlphaMed Press 2020 SIGNIFICANCE STATEMENT: The current study reveals a novel link between DNMT3B and the metabolic flux in human ESCs. Loss of DNMT3B disrupts the cells mitochondrial fusion and fission balance, reduces mitochondrial DNA levels, and elicits a switch from glycolysis to oxidative phosphorylation. The authors further show that loss of DNMT3B leads to an overexpression and hyperactivity of isocitrate dehydrogenases and buildup of α-ketoglutarate, as well as a significant upregulation of transcription factors during early neural differentiation. The observed increase in α-ketoglutarate levels can be reversed by re-expression of DNMT3B, demonstrating that its dysregulation is a direct consequence of DNMT3B-deficiency.

DOI: https://doi.org/10.1002/stem.3256
Trends Genet. 2020 Jul 13. pii: S0168-9525(20)30155-4. [Epub ahead of print]

Mitochondrial Diseases: A Diagnostic Revolution.

Katherine R Schon, Thiloka Ratnaike, Jelle van den Ameele, Rita Horvath, Patrick F Chinnery.

  Mitochondrial disorders have emerged as a common cause of inherited disease, but are traditionally viewed as being difficult to diagnose clinically, and even more difficult to comprehensively characterize at the molecular level. However, new sequencing approaches, particularly whole-genome sequencing (WGS), have dramatically changed the landscape. The combined analysis of nuclear and mitochondrial DNA (mtDNA) allows rapid diagnosis for the vast majority of patients, but new challenges have emerged. We review recent discoveries that will benefit patients and families, and highlight emerging questions that remain to be resolved.

Keywords:  genetic diagnosis; mitochondrial disease; molecular diagnostics; mtDNA mutation; whole-genome sequencing

DOI:  https://doi.org/10.1016/j.tig.2020.06.009
Nat Immunol. 2020 Jul 13.

Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen.

Santosha A Vardhana, Madeline A Hwee, Mirela Berisa, Daniel K Wells, Kathryn E Yost, Bryan King, Melody Smith, Pamela S Herrera, Howard Y Chang, Ansuman T Satpathy, Marcel R M van den Brink, Justin R Cross, Craig B Thompson.

The majority of tumor-infiltrating T cells exhibit a terminally exhausted phenotype, marked by a loss of self-renewal capacity. How repetitive antigenic stimulation impairs T cell self-renewal remains poorly defined. Here, we show that persistent antigenic stimulation impaired ADP-coupled oxidative phosphorylation. The resultant bioenergetic compromise blocked proliferation by limiting nucleotide triphosphate synthesis. Inhibition of mitochondrial oxidative phosphorylation in activated T cells was sufficient to suppress proliferation and upregulate genes linked to T cell exhaustion. Conversely, prevention of mitochondrial oxidative stress during chronic T cell stimulation allowed sustained T cell proliferation and induced genes associated with stem-like progenitor T cells. As a result, antioxidant treatment enhanced the anti-tumor efficacy of chronically stimulated T cells. These data reveal that loss of ATP production through oxidative phosphorylation limits T cell proliferation and effector function during chronic antigenic stimulation. Furthermore, treatments that maintain redox balance promote T cell self-renewal and enhance anti-tumor immunity.

DOI: https://doi.org/10.1038/s41590-020-0725-2
Cancer Sci. 2020 Jul 17.

Mechanism of tumor-suppressive cell competition in flies.

Hiroshi Kanda, Tatsushi Igaki.

  Oncogenic mutations often trigger anti-tumor cellular response such as induction of apoptosis or cellular senescence. Studies in the last decade have identified the presence of the third guardian against mutation-induced tumorigenesis, namely 'cell competition'. Cell competition is a context-dependent cell elimination whereby cells with higher fitness eliminate neighboring cells with lower fitness by inducing cell death. While oncogene-induced apoptosis or oncogene-induced senescence acts as a cell-autonomous tumor suppressor, cell competition protects tissue from tumorigenesis via cell-cell communication. For instance, in Drosophila epithelium, oncogenic cells with cell-polarity mutations overproliferate and develop into tumors on their own but are eliminated from the tissue when surrounded by wild-type cells. Genetic studies in flies have unraveled that such tumor-suppressive cell competition is regulated by at least three mechanisms: direct cell-cell interaction between polarity-deficient cells and wild-type cells, secreted factors from epithelial cells, and systemic factors from distant organs. Molecular manipulation of tumor-suppressive cell competition could provide a novel therapeutic strategy against human cancers.

Keywords:   Drosophila ; Cell competition; tumor suppression

DOI:  https://doi.org/10.1111/cas.14575
Cell Rep. 2020 Jul 14. pii: S2211-1247(20)30886-X. [Epub ahead of print]32(2): 107905

Small Molecule Enhancers of Endosome-to-Cytosol Import Augment Anti-tumor Immunity.

Patrycja Kozik, Marine Gros, Daniel N Itzhak, Leonel Joannas, Sandrine Heurtebise-Chrétien, Patrycja A Krawczyk, Pablo Rodríguez-Silvestre, Andrés Alloatti, Joao Gamelas Magalhaes, Elaine Del Nery, Georg H H Borner, Sebastian Amigorena.

  Cross-presentation of antigens by dendritic cells (DCs) is critical for initiation of anti-tumor immune responses. Yet, key steps involved in trafficking of antigens taken up by DCs remain incompletely understood. Here, we screen 700 US Food and Drug Administration (FDA)-approved drugs and identify 37 enhancers of antigen import from endolysosomes into the cytosol. To reveal their mechanism of action, we generate proteomic organellar maps of control and drug-treated DCs (focusing on two compounds, prazosin and tamoxifen). By combining organellar mapping, quantitative proteomics, and microscopy, we conclude that import enhancers undergo lysosomal trapping leading to membrane permeation and antigen release. Enhancing antigen import facilitates cross-presentation of soluble and cell-associated antigens. Systemic administration of prazosin leads to reduced growth of MC38 tumors and to a synergistic effect with checkpoint immunotherapy in a melanoma model. Thus, inefficient antigen import into the cytosol limits antigen cross-presentation, restraining the potency of anti-tumor immune responses and efficacy of checkpoint blockers.

Keywords:  cross-presentation; dendritic cells; dynamic organellar maps; immunotherapy; lysosomes; organellar proteomics; small molecule screening

DOI:  https://doi.org/10.1016/j.celrep.2020.107905
Trends Cancer. 2020 Jul 15. pii: S2405-8033(20)30189-8. [Epub ahead of print]

Targeting EMT in Cancer with Repurposed Metabolic Inhibitors.

Vignesh Ramesh, Thomas Brabletz, Paolo Ceppi.

  Epithelial-to-mesenchymal transition (EMT) determines the most lethal features of cancer, metastasis formation and chemoresistance, and therefore represents an attractive target in oncology. However, direct targeting of EMT effector molecules is, in most cases, pharmacologically challenging. Since emerging research has highlighted the distinct metabolic circuits involved in EMT, we propose the use of metabolism-specific inhibitors, FDA approved or under clinical trials, as a drug repurposing approach to target EMT in cancer. Metabolism-inhibiting drugs could be coupled with standard chemo- or immunotherapy to combat EMT-driven resistant and aggressive cancers.

Keywords:  chemoresistance; drug repurposing; epithelial–mesenchymal transition; metabolic inhibitor; partial EMT

DOI:  https://doi.org/10.1016/j.trecan.2020.06.005
Mitochondrion. 2020 Jul 13. pii: S1567-7249(20)30161-6. [Epub ahead of print]

Effects of dietary iron restriction on kidney mitochondria function and oxidative stress in streptozotocin-diabetic rats.

Donovan J Peña-Montes, Maribel Huerta-Cervantes, Mónica Ríos-Silva, Xóchitl Trujillo, Christian Cortés-Rojo, Miguel Huerta, Alfredo Saavedra-Molina.

  Diabetes mellitus is characterized by chronic hyperglycemia causing mitochondrial dysfunction and kidney iron overload has been observed during diabetes. We evaluated the effects of an iron-restricted diet (IRD) on mitochondrial function, oxidative stress, and mitochondrial iron levels in the kidneys of Wistar rats with streptozotocin-induced diabetes. IRD ameliorated mitochondrial dysfunction in diabetic rats by restoring mitochondrial respiration and respiratory complex activity, improving oxidative stress and glutathione status in kidney mitochondria. We also observed mitochondrial iron overload. Our data suggest that elevated iron levels were attenuated by IRD, resulting in modulation of oxidative stress and mitochondrial function in the kidney.

Keywords:  diabetes mellitus; iron restriction; kidney; mitochondria; oxidative stress

DOI:  https://doi.org/10.1016/j.mito.2020.07.001
Nat Ecol Evol. 2020 Jul 13.

Phylogenetic analyses with systematic taxon sampling show that mitochondria branch within Alphaproteobacteria.

Lu Fan, Dingfeng Wu, Vadim Goremykin, Jing Xiao, Yanbing Xu, Sriram Garg, Chuanlun Zhang, William F Martin, Ruixin Zhu.

Though it is well accepted that mitochondria originated from an alphaproteobacteria-like ancestor, the phylogenetic relationship of the mitochondrial endosymbiont to extant Alphaproteobacteria is yet unresolved. The focus of much debate is whether the affinity between mitochondria and fast-evolving alphaproteobacterial lineages reflects true homology or artefacts. Approaches such as site exclusion have been claimed to mitigate compositional heterogeneity between taxa, but this comes at the cost of information loss, and the reliability of such methods is so far unproven. Here we demonstrate that site-exclusion methods produce erratic phylogenetic estimates of mitochondrial origin. Thus, previous phylogenetic hypotheses on the origin of mitochondria based on pretreated datasets should be re-evaluated. We applied alternative strategies to reduce phylogenetic noise by systematic taxon sampling while keeping site substitution information intact. Cross-validation based on a series of trees placed mitochondria robustly within Alphaproteobacteria, sharing an ancient common ancestor with Rickettsiales and currently unclassified marine lineages.

DOI: https://doi.org/10.1038/s41559-020-1239-x
Nat Cancer. 2020 Jan;1(1): 28-45

L1CAM defines the regenerative origin of metastasis-initiating cells in colorectal cancer.

Karuna Ganesh, Harihar Basnet, Yasemin Kaygusuz, Ashley M Laughney, Lan He, Roshan Sharma, Kevin P O'Rourke, Vincent P Reuter, Yun-Han Huang, Mesruh Turkekul, Ekrem Emrah, Ignas Masilionis, Katia Manova-Todorova, Martin R Weiser, Leonard B Saltz, Julio Garcia-Aguilar, Richard Koche, Scott W Lowe, Dana Pe'er, Jinru Shia, Joan Massagué.

Metastasis-initiating cells with stem-like properties drive cancer lethality, yet their origins and relationship to primary-tumor-initiating stem cells are not known. We show that L1CAM+ cells in human colorectal cancer (CRC) have metastasis-initiating capacity, and we define their relationship to tissue regeneration. L1CAM is not expressed in the homeostatic intestinal epithelium, but is induced and required for epithelial regeneration following colitis and in CRC organoid growth. By using human tissues and mouse models, we show that L1CAM is dispensable for adenoma initiation but required for orthotopic carcinoma propagation, liver metastatic colonization and chemoresistance. L1CAMhigh cells partially overlap with LGR5high stem-like cells in human CRC organoids. Disruption of intercellular epithelial contacts causes E-cadherin-REST transcriptional derepression of L1CAM, switching chemoresistant CRC progenitors from an L1CAMlow to an L1CAMhigh state. Thus, L1CAM dependency emerges in regenerative intestinal cells when epithelial integrity is lost, a phenotype of wound healing deployed in metastasis-initiating cells.

DOI: https://doi.org/10.1038/s43018-019-0006-x
Nat Commun. 2020 Jul 15. 11(1): 3546

ITLN1 modulates invasive potential and metabolic reprogramming of ovarian cancer cells in omental microenvironment.

Chi-Lam Au-Yeung, Tsz-Lun Yeung, Abhinav Achreja, Hongyun Zhao, Kay-Pong Yip, Suet-Ying Kwan, Michaela Onstad, Jianting Sheng, Ying Zhu, Dodge L Baluya, Ngai-Na Co, Angela Rynne-Vidal, Rosemarie Schmandt, Matthew L Anderson, Karen H Lu, Stephen T C Wong, Deepak Nagrath, Samuel C Mok.

Advanced ovarian cancer usually spreads to the omentum. However, the omental cell-derived molecular determinants modulating its progression have not been thoroughly characterized. Here, we show that circulating ITLN1 has prognostic significance in patients with advanced ovarian cancer. Further studies demonstrate that ITLN1 suppresses lactotransferrin's effect on ovarian cancer cell invasion potential and proliferation by decreasing MMP1 expression and inducing a metabolic shift in metastatic ovarian cancer cells. Additionally, ovarian cancer-bearing mice treated with ITLN1 demonstrate marked decrease in tumor growth rates. These data suggest that downregulation of mesothelial cell-derived ITLN1 in the omental tumor microenvironment facilitates ovarian cancer progression.

DOI: https://doi.org/10.1038/s41467-020-17383-2
Nat Commun. 2020 Jul 15. 11(1): 3547

Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling.

Eman Khatib-Massalha, Suditi Bhattacharya, Hassan Massalha, Adi Biram, Karin Golan, Orit Kollet, Anju Kumari, Francesca Avemaria, Ekaterina Petrovich-Kopitman, Shiri Gur-Cohen, Tomer Itkin, Isabell Brandenburger, Asaf Spiegel, Ziv Shulman, Zachary Gerhart-Hines, Shalev Itzkovitz, Matthias Gunzer, Stefan Offermanns, Ronen Alon, Amiram Ariel, Tsvee Lapidot.

Neutrophils provide first line of host defense against bacterial infections utilizing glycolysis for their effector functions. How glycolysis and its major byproduct lactate are triggered in bone marrow (BM) neutrophils and their contribution to neutrophil mobilization in acute inflammation is not clear. Here we report that bacterial lipopolysaccharides (LPS) or Salmonella Typhimurium triggers lactate release by increasing glycolysis, NADPH-oxidase-mediated reactive oxygen species and HIF-1α levels in BM neutrophils. Increased release of BM lactate preferentially promotes neutrophil mobilization by reducing endothelial VE-Cadherin expression, increasing BM vascular permeability via endothelial lactate-receptor GPR81 signaling. GPR81-/- mice mobilize reduced levels of neutrophils in response to LPS, unless rescued by VE-Cadherin disrupting antibodies. Lactate administration also induces release of the BM neutrophil mobilizers G-CSF, CXCL1 and CXCL2, indicating that this metabolite drives neutrophil mobilization via multiple pathways. Our study reveals a metabolic crosstalk between lactate-producing neutrophils and BM endothelium, which controls neutrophil mobilization under bacterial infection.

DOI: https://doi.org/10.1038/s41467-020-17402-2
Nat Struct Mol Biol. 2020 Jul 13.

A redox switch regulates the structure and function of anti-apoptotic BFL-1.

Kyle J Korshavn, Thomas E Wales, Gregory H Bird, John R Engen, Loren D Walensky.

Apoptosis is regulated by BCL-2 family proteins. Anti-apoptotic members suppress cell death by deploying a surface groove to capture the critical BH3 α-helix of pro-apoptotic members. Cancer cells hijack this mechanism by overexpressing anti-apoptotic BCL-2 family proteins to enforce cellular immortality. We previously identified and harnessed a unique cysteine (C55) in the groove of anti-apoptotic BFL-1 to selectively neutralize its oncogenic activity using a covalent stapled-peptide inhibitor. Here, we find that disulfide bonding between a native cysteine pair at the groove (C55) and C-terminal α9 helix (C175) of BFL-1 operates as a redox switch to control the accessibility of the anti-apoptotic pocket. Reducing the C55-C175 disulfide triggers α9 release, which promotes mitochondrial translocation, groove exposure for BH3 interaction and inhibition of mitochondrial permeabilization by pro-apoptotic BAX. C55-C175 disulfide formation in an oxidative cellular environment abrogates the ability of BFL-1 to bind BH3 domains. Thus, we identify a mechanism of conformational control of BFL-1 by an intramolecular redox switch.

DOI: https://doi.org/10.1038/s41594-020-0458-9
Nat Biotechnol. 2020 Jul 13.

Metabolic engineering generates a transgene-free safety switch for cell therapy.

Volker Wiebking, James O Patterson, Renata Martin, Monica K Chanda, Ciaran M Lee, Waracharee Srifa, Gang Bao, Matthew H Porteus.

Safeguard mechanisms can ameliorate the potential risks associated with cell therapies but currently rely on the introduction of transgenes. This limits their application owing to immunogenicity or transgene silencing. We aimed to create a control mechanism for human cells that is not mediated by a transgene. Using genome editing methods, we disrupt uridine monophosphate synthetase (UMPS) in the pyrimidine de novo synthesis pathway in cell lines, pluripotent cells and primary human T cells. We show that this makes proliferation dependent on external uridine and enables us to control cell growth by modulating the uridine supply, both in vitro and in vivo after transplantation in xenograft models. Additionally, disrupting this pathway creates resistance to 5-fluoroorotic acid, which enables positive selection of UMPS-knockout cells. We envision that this approach will add an additional level of safety to cell therapies and therefore enable the development of approaches with higher risks, especially those that are intended for limited treatment durations.

DOI: https://doi.org/10.1038/s41587-020-0580-6
Nat Commun. 2020 Jul 14. 11(1): 3520

PRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis.

Slim Mzoughi, Jia Yi Fong, David Papadopoli, Cheryl M Koh, Laura Hulea, Paolo Pigini, Federico Di Tullio, Giuseppe Andreacchio, Michal Marek Hoppe, Heike Wollmann, Diana Low, Matias J Caldez, Yanfen Peng, Denis Torre, Julia N Zhao, Oro Uchenunu, Gabriele Varano, Corina-Mihaela Motofeanu, Manikandan Lakshmanan, Shun Xie Teo, Cheng Mun Wun, Giovanni Perini, Soo Yong Tan, Chee Bing Ong, Muthafar Al-Haddawi, Ravisankar Rajarethinam, Susan Swee-Shan Hue, Soon Thye Lim, Choon Kiat Ong, Dachuan Huang, Siok-Bian Ng, Emily Bernstein, Dan Hasson, Keng Boon Wee, Philipp Kaldis, Anand Jeyasekharan, David Dominguez-Sola, Ivan Topisirovic, Ernesto Guccione.

PRDM (PRDI-BF1 and RIZ homology domain containing) family members are sequence-specific transcriptional regulators involved in cell identity and fate determination, often dysregulated in cancer. The PRDM15 gene is of particular interest, given its low expression in adult tissues and its overexpression in B-cell lymphomas. Despite its well characterized role in stem cell biology and during early development, the role of PRDM15 in cancer remains obscure. Herein, we demonstrate that while PRDM15 is largely dispensable for mouse adult somatic cell homeostasis in vivo, it plays a critical role in B-cell lymphomagenesis. Mechanistically, PRDM15 regulates a transcriptional program that sustains the activity of the PI3K/AKT/mTOR pathway and glycolysis in B-cell lymphomas. Abrogation of PRDM15 induces a metabolic crisis and selective death of lymphoma cells. Collectively, our data demonstrate that PRDM15 fuels the metabolic requirement of B-cell lymphomas and validate it as an attractive and previously unrecognized target in oncology.

DOI: https://doi.org/10.1038/s41467-020-17064-0
Cancer Cell. 2020 Jul 13. pii: S1535-6108(20)30313-5. [Epub ahead of print]38(1): 17-20

NOTCH Your Usual Suspect: MYC Charged with Controlling Neuroendocrine Cell-Fate in Small Cell Lung Cancer.

Jin Ng, Kate D Sutherland.

Small cell lung cancer (SCLC) is highly heterogeneous. In this issue of Cancer Cell, Ireland et al. demonstrate that MYC mediates neuroendocrine cell plasticity in SCLC by activating NOTCH signaling. This MYC-NOTCH axis controls the dynamic behavior of tumor cells, resulting in the co-existence of SCLC subtypes within individual tumors.

DOI: https://doi.org/10.1016/j.ccell.2020.06.009
Curr Biol. 2020 Jul 09. pii: S0960-9822(20)30857-5. [Epub ahead of print]

Periodic Oscillations of Myosin-II Mechanically Proofread Cell-Cell Connections to Ensure Robust Formation of the Cardiac Vessel.

Shaobo Zhang, Xiang Teng, Yusuke Toyama, Timothy E Saunders.

  Actomyosin networks provide the major contractile machinery for regulating cell and tissue morphogenesis during development. These networks undergo dynamic rearrangements, enabling cells to have a broad range of mechanical actions. How cells integrate different mechanical stimuli to accomplish complicated tasks in vivo remains unclear. Here, we explore this problem in the context of cell matching, where individual cells form precise inter-cellular connections between partner cells. To study the dynamic roles of actomyosin networks in regulating precise cell matching, we focused on the process of heart formation during Drosophila embryogenesis, where selective filopodia-binding adhesions ensure precise cell alignment. We find that non-muscle Myosin II clusters periodically oscillate within cardioblasts with ~4-min intervals. We observe that filopodia dynamics-including protrusions, retraction, binding stabilization, and binding separation-are correlated with the periodic localization of Myosin II clusters at the cell leading edge. Perturbing the Myosin II activity and oscillatory pattern alters the filopodia properties and binding dynamics and results in mismatched cardioblasts. By simultaneously changing the activity of Myosin II and filopodia adhesion levels, we further demonstrate that levels of Myosin II and adhesion are balanced to ensure precise connectivity between cardioblasts. Combined, we propose a mechanical proofreading machinery of robust cell matching, whereby oscillations of Myosin II within cardioblasts periodically probe filopodia adhesion strength and ensure correct cell-cell connection formation.

Keywords:  Drosophila heart development; Myosin II; actomyosin dynamics; cell matching; cell-cell adhesion; filopodia; proofreading

DOI:  https://doi.org/10.1016/j.cub.2020.06.041
Nat Commun. 2020 Jul 17. 11(1): 3588

Tumors induce de novo steroid biosynthesis in T cells to evade immunity.

Bidesh Mahata, Jhuma Pramanik, Louise van der Weyden, Krzysztof Polanski, Gozde Kar, Angela Riedel, Xi Chen, Nuno A Fonseca, Kousik Kundu, Lia S Campos, Edward Ryder, Graham Duddy, Izabela Walczak, Klaus Okkenhaug, David J Adams, Jacqueline D Shields, Sarah A Teichmann.

Tumors subvert immune cell function to evade immune responses, yet the complex mechanisms driving immune evasion remain poorly understood. Here we show that tumors induce de novo steroidogenesis in T lymphocytes to evade anti-tumor immunity. Using a transgenic steroidogenesis-reporter mouse line we identify and characterize de novo steroidogenic immune cells, defining the global gene expression identity of these steroid-producing immune cells and gene regulatory networks by using single-cell transcriptomics. Genetic ablation of T cell steroidogenesis restricts primary tumor growth and metastatic dissemination in mouse models. Steroidogenic T cells dysregulate anti-tumor immunity, and inhibition of the steroidogenesis pathway is sufficient to restore anti-tumor immunity. This study demonstrates T cell de novo steroidogenesis as a mechanism of anti-tumor immunosuppression and a potential druggable target.

DOI: https://doi.org/10.1038/s41467-020-17339-6
Cancer Res. 2020 Jul 13. pii: canres.2486.2019. [Epub ahead of print]

Glucose-6-phosphate dehydrogenase is not essential for K-Ras-driven tumor growth or metastasis.

Jonathan M Ghergurovich, Mark Esposito, Zihong Chen, Joshua Z Wang, Vrushank Bhatt, Taijin Lan, Eileen White, Yibin Kang, Jessie Yanxiang Guo, Joshua D Rabinowitz.

The enzyme glucose-6-phosphate dehydrogenase (G6PD) is a major contributor to NADPH production and redox homeostasis and its expression is upregulated and correlated with negative patient outcomes in multiple human cancer types. Despite these associations, whether G6PD is essential for tumor initiation, growth, or metastasis remains unclear. Here we employ modern genetic tools to evaluate the role of G6PD in lung, breast, and colon cancer driven by oncogenic K-Ras. Human HCT116 colorectal cancer cells lacking G6PD exhibited metabolic indicators of oxidative stress but developed into subcutaneous xenografts with growth comparable to that of wild-type controls. In a genetically engineered mouse model of non-small-cell lung cancer driven by K-Ras G12D and p53-deficiency, G6PD knockout did not block formation or proliferation of primary lung tumors. In MDA-MB 231-derived human triple-negative breast cancer cells implanted as orthotopic xenografts, loss of G6PD modestly decreased primary site growth without ablating spontaneous metastasis to the lung and moderately impaired the ability of breast cancer cells to colonize the lung when delivered via tail vein injection. Thus, in the studied K-Ras tumor models, G6PD is not strictly essential for tumorigenesis and at most modestly promotes disease progression.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-2486