bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2019–03–24
47 papers selected by
Christian Frezza, , University of Cambridge, MRC Cancer Unit
  1. CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain.
  2. S100A4 alters metabolism and promotes invasion of lung cancer cells by up-regulating mitochondrial complex I protein NDUFS2.
  3. Glutamine regulates mitochondrial uncoupling protein 2 to promote glutaminolysis in neuroblastoma cells.
  4. Metabolic gatekeepers to safeguard against autoimmunity and oncogenic B cell transformation.
  5. Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7.
  6. Regulation and Function of Mitochondria-Lysosome Membrane Contact Sites in Cellular Homeostasis.
  7. Spatial-fluxomics provides a subcellular-compartmentalized view of reductive glutamine metabolism in cancer cells.
  8. PSEN2 (presenilin 2) mutants linked to familial Alzheimer disease impair autophagy by altering Ca2+ homeostasis.
  9. Mitochondrial fission-induced mtDNA stress promotes tumor-associated macrophage infiltration and HCC progression.
  10. Mitochondrial protein-induced stress triggers a global adaptive transcriptional programme.
  11. Cancer mutational burden is shaped by G4 DNA, replication stress and mitochondrial dysfunction.
  12. LETM1 is required for mitochondrial homeostasis and cellular viability (Review).
  13. Fibroblast growth factor 21 controls mitophagy and muscle mass.
  14. Activation of mTORC1/PGC1 axis promotes mitochondrial biogenesis and induces cellular senescence in the lung epithelium.
  15. Temperature dependence of mitoflash biogenesis in cardiac mitochondria.
  16. Deficiency of Mitophagy Receptor FUNDC1 Impairs Mitochondrial Quality and Aggravates Dietary-Induced Obesity and Metabolic Syndrome.
  17. The second genome: Effects of the mitochondrial genome on cancer progression.
  18. Loss of MIEF1/MiD51 confers susceptibility to BAX-mediated cell death and PINK1-PRKN-dependent mitophagy.
  19. O-GlcNAcylation enhances double strand break repair, promotes cancer cell proliferation and prevents therapy-induced senescence in irradiated tumors.
  20. F-actin dynamics regulates mammalian organ growth and cell fate maintenance.
  21. Mitochondria in precision medicine; linking bioenergetics and metabolomics in platelets.
  22. MDM2 Integrates Cellular Respiration and Apoptotic Signaling through NDUFS1 and the Mitochondrial Network.
  23. Dysregulated Redox Regulation Contributes to Nuclear EGFR Localization and Pathogenicity in Lung Cancer.
  24. Dimethyl Fumarate Disrupts Human Innate Immune Signaling by Targeting the IRAK4-MyD88 Complex.
  25. The plant triterpenoid celastrol blocks PINK1-dependent mitophagy by disrupting PINK1's association with the mitochondrial protein TOM20.
  26. Developmental and sex differences in cardiac tolerance to ischemia/reperfusion injury: the role of mitochondria.
  27. Low-dose 2-deoxyglucose and metformin synergically inhibit proliferation of human polycystic kidney cells by modulating glucose metabolism.
  28. ROR1-CAVIN3 interaction required for caveolae-dependent endocytosis and pro-survival signaling in lung adenocarcinoma.
  29. A battle for transmission: the cooperative and selfish animal mitochondrial genomes.
  30. Coming together to define membrane contact sites.
  31. Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A model.
  32. Multi-dimensional Transcriptional Remodeling by Physiological Insulin In Vivo.
  33. Redox regulation of ER and mitochondrial Ca2+ signaling in cell survival and death.
  34. mTOR signaling in mouse models of accelerated aging.
  35. PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia.
  36. A nuclear phosphoinositide kinase complex regulates p53.
  37. Epigenetic regulation by endogenous metabolite pharmacology.
  38. Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion.
  39. Mitochondrial carrier protein overloading and misfolding induce aggresomes and proteostatic adaptations in the cytosol.
  40. Entosis Controls a Developmental Cell Clearance in C. elegans.
  41. Succinylation Links Metabolism to Protein Functions.
  42. Targeting glutamine-addiction and overcoming CDK4/6 inhibitor resistance in human esophageal squamous cell carcinoma.
  43. Serine and Methionine Metabolism: Vulnerabilities in Lethal Prostate Cancer.
  44. Structure and Mechanisms of F-Type ATP Synthases.
  45. Glycine Protects against Hypoxic-Ischemic Brain Injury by Regulating Mitochondria-Mediated Autophagy via the AMPK Pathway.
  46. The expanding landscape of 'oncohistone' mutations in human cancers.
  47. AMPK activation protects against diet induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose tissue.
  1. Cancer Metab. 2019 ;7 2
    CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain.
    Luke W Thomas, Jenna M Stephen, Cinzia Esposito, Simon Hoer, Robin Antrobus, Afshan Ahmed, Hasan Al-Habib, Margaret Ashcroft.
       Background: Tumour cells rely on glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) to survive. Thus, mitochondrial OXPHOS has become an increasingly attractive area for therapeutic exploitation in cancer. However, mitochondria are required for intracellular oxygenation and normal physiological processes, and it remains unclear which mitochondrial molecular mechanisms might provide therapeutic benefit. Previously, we discovered that coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4) is critical for regulating intracellular oxygenation and required for the cellular response to hypoxia (low oxygenation) in tumour cells through molecular mechanisms that we do not yet fully understand. Overexpression of CHCHD4 in human cancers correlates with increased tumour progression and poor patient survival.
    Results: Here, we show that elevated CHCHD4 expression provides a proliferative and metabolic advantage to tumour cells in normoxia and hypoxia. Using stable isotope labelling with amino acids in cell culture (SILAC) and analysis of the whole mitochondrial proteome, we show that CHCHD4 dynamically affects the expression of a broad range of mitochondrial respiratory chain subunits from complex I-V, including multiple subunits of complex I (CI) required for complex assembly that are essential for cell survival. We found that loss of CHCHD4 protects tumour cells from respiratory chain inhibition at CI, while elevated CHCHD4 expression in tumour cells leads to significantly increased sensitivity to CI inhibition, in part through the production of mitochondrial reactive oxygen species (ROS).
    Conclusions: Our study highlights an important role for CHCHD4 in regulating tumour cell metabolism and reveals that CHCHD4 confers metabolic vulnerabilities to tumour cells through its control of the mitochondrial respiratory chain and CI biology.
    Keywords:  Coiled-coil-helix-coiled-coil-helix domain-containing 4 (CHCHD4); Complex I; Disulfide relay system; HIF-1α; Hypoxia; Mitochondria; Respiratory chain; Tumour growth; Tumour metabolism
    DOI:  https://doi.org/10.1186/s40170-019-0194-y
  2. J Biol Chem. 2019 Mar 18. pii: jbc.RA118.004365. [Epub ahead of print]
    S100A4 alters metabolism and promotes invasion of lung cancer cells by up-regulating mitochondrial complex I protein NDUFS2.
    Lili Liu, Lei Qi, Teresa Knifley, Dava W Piecoro, Piotr Rychahou, Jinpeng Liu, Mihail I Mitov, Jeremiah Martin, Chi Wang, Jianrong Wu, Heidi L Weiss, D Allan Butterfield, B Mark Evers, Kathleen L O'Connor, Min Chen.
      It is generally accepted that alterations in metabolism are critical for the metastatic process; however, the mechanisms by which these metabolic changes are controlled by the major drivers of the metastatic process remain elusive. Here, we found that S100 calcium-binding protein A4 (S100A4), a major metastasis-promoting protein, confers metabolic plasticity to drive tumor invasion and metastasis of non-small cell lung cancer cells. Investigating how S100A4 regulates metabolism, we found that S100A4 depletion decreases oxygen consumption rates, mitochondrial activity, and ATP production and also shifts cell metabolism to higher glycolytic activity. We further identified that the 49 KD mitochondrial complex I subunit NADH dehydrogenase (ubiquinone) Fe-S protein 2 (NDUFS2) is regulated in an S100A4-dependent manner and that S100A4 and NDUFS2 exhibit co-occurrence at significant levels in various cancer types as determined by database-driven analysis of genomes in clinical samples using cBioPortal for Cancer Genomics. Importantly, we noted that S100A4 or NDUFS2 silencing inhibits mitochondrial complex I activity, reduces cellular ATP level, decreases invasive capacity in three-dimensional (3D) growth, and dramatically decreases metastasis rates as well as tumor growth in vivo. Finally, we provide evidence that cells depleted in S100A4 or NDUFS2 shift their metabolism toward glycolysis by up-regulating hexokinase expression and that suppressing S100A4 signaling sensitizes lung cancer cells to glycolysis inhibition. Our findings uncover a novel S100A4 function and highlight its importance in controlling NDUFS2 expression to regulate the plasticity of mitochondrial metabolism and thereby promote the invasive and metastatic capacity in lung cancer.
    Keywords:  Fibroblast specific protein-1; NADH:ubiquinone oxidoreductase core subunit S2 (NDUFS2); S100 calcium-binding protein A4 (S100A4); S100 proteins; energy metabolism; glycolysis; invasion; lung cancer; metastasis; metastasis-1; mitochondria; mitochondrial complex I; mitochondrial respiratory chain complex
    DOI:  https://doi.org/10.1074/jbc.RA118.004365
  3. Biochim Biophys Acta Bioenerg. 2019 Mar 15. pii: S0005-2728(18)30239-1. [Epub ahead of print]
    Glutamine regulates mitochondrial uncoupling protein 2 to promote glutaminolysis in neuroblastoma cells.
    Anne Rupprecht, Rudolf Moldzio, Bernadette Mödl, Elena E Pohl.
      Mitochondrial uncoupling protein 2 (UCP2) is highly abundant in fast proliferating cells that utilize aerobic glycolysis such as stem cells, cancer cells and cells of the immune system. However, its function is a longstanding conundrum. Taking into account the strict regulation and unusual short life time of the protein, we propose that UCP2 acts as a "signal protein" under nutrient shortage in cancer cells. We reveal that glutamine shortage induces a fast and reversible downregulation of UCP2, decrease of the metabolic activity and proliferation of neuroblastoma cells, which are regulated by glutamine per se but not by glutamine metabolism. Our findings indicate a very fast (within 1 h) metabolic adaptation, which allowed the cell to survive by either shifting its metabolism to the use of the alternative fuel glutamine or going into a reversible more quiescent state. The results imply that UCP2 facilitates glutamine utilization as an energetic fuel, thereby providing metabolic flexibility during glucose shortage. Targeting UCP2 by drugs could intervene with cancer cell metabolism and may represent a new strategy for the treatment of cancers resistant to other therapies.
    DOI:  https://doi.org/10.1016/j.bbabio.2019.03.006
  4. Nat Rev Immunol. 2019 Mar 19.
    Metabolic gatekeepers to safeguard against autoimmunity and oncogenic B cell transformation.
    Markus Müschen.
      B cells face multiple restrictions on glucose and energy metabolism. Their lineage-determining transcription factors repress glucose uptake and pentose phosphate pathway activity, while their low numbers of mitochondria and small cytoplasmic volume set narrow limits for mitochondrial ATP production and autophagy as alternative energy sources. During activation, B cells can balance temporary increases of energy expenditure. However, permanent hyperactivation of kinases, for instance, downstream of an autoreactive B cell receptor (BCR) or a transforming oncogene, can cause energy stress and cell death. Here, I propose that B cell-intrinsic restriction of ATP represents a safeguard to eliminate autoreactive or pre-malignant B cells. If the metabolic gatekeepers are compromised, influx of additional glucose may fuel permanent increases in metabolic demands and pathological B cell proliferation, driven by an autoreactive BCR or a transforming oncogene.
    DOI:  https://doi.org/10.1038/s41577-019-0154-3
  5. EMBO Mol Med. 2019 Mar 18. pii: e9561. [Epub ahead of print]
    Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7.
    Karthik Mohanraj, Michal Wasilewski, Cristiane Benincá, Dominik Cysewski, Jaroslaw Poznanski, Paulina Sakowska, Zaneta Bugajska, Markus Deckers, Sven Dennerlein, Erika Fernandez-Vizarra, Peter Rehling, Michal Dadlez, Massimo Zeviani, Agnieszka Chacinska.
      Nuclear and mitochondrial genome mutations lead to various mitochondrial diseases, many of which affect the mitochondrial respiratory chain. The proteome of the intermembrane space (IMS) of mitochondria consists of several important assembly factors that participate in the biogenesis of mitochondrial respiratory chain complexes. The present study comprehensively analyzed a recently identified IMS protein cytochrome c oxidase assembly factor 7 (COA7), or RESpiratory chain Assembly 1 (RESA1) factor that is associated with a rare form of mitochondrial leukoencephalopathy and complex IV deficiency. We found that COA7 requires the mitochondrial IMS import and assembly (MIA) pathway for efficient accumulation in the IMS We also found that pathogenic mutant versions of COA7 are imported slower than the wild-type protein, and mislocalized proteins are degraded in the cytosol by the proteasome. Interestingly, proteasome inhibition rescued both the mitochondrial localization of COA7 and complex IV activity in patient-derived fibroblasts. We propose proteasome inhibition as a novel therapeutic approach for a broad range of mitochondrial pathologies associated with the decreased levels of mitochondrial proteins.
    Keywords:  COA7/RESA1; mitochondrial disease; proteasome; protein degradation; protein import
    DOI:  https://doi.org/10.15252/emmm.201809561
  6. Trends Cell Biol. 2019 Mar 18. pii: S0962-8924(19)30026-1. [Epub ahead of print]
    Regulation and Function of Mitochondria-Lysosome Membrane Contact Sites in Cellular Homeostasis.
    Yvette C Wong, Soojin Kim, Wesley Peng, Dimitri Krainc.
      Mitochondrial and lysosomal function are intricately related and critical for maintaining cellular homeostasis, as highlighted by multiple diseases linked to dysfunction of both organelles. Recent work using high-resolution microscopy demonstrates the dynamic formation of inter-organelle membrane contact sites between mitochondria and lysosomes, allowing for their direct interaction in a pathway distinct from mitophagy or lysosomal degradation of mitochondrial-derived vesicles. Mitochondria-lysosome contact site tethering is mechanistically regulated by mitochondrial proteins promoting Rab7 GTP hydrolysis, and allows for the bidirectional crosstalk between mitochondria and lysosomes and the regulation of their organelle network dynamics, including mitochondrial fission. In this review, we summarize recent advances in mitochondria-lysosome contact site regulation and function, and discuss their potential roles in cellular homeostasis and various human diseases.
    Keywords:  Rab7 GTP hydrolysis; disease; inter-organelle membrane contact site; lysosome; mitochondria; mitochondrial fission; organelle dynamics
    DOI:  https://doi.org/10.1016/j.tcb.2019.02.004
  7. Nat Commun. 2019 Mar 22. 10(1): 1351
    Spatial-fluxomics provides a subcellular-compartmentalized view of reductive glutamine metabolism in cancer cells.
    Won Dong Lee, Dzmitry Mukha, Elina Aizenshtein, Tomer Shlomi.
      The inability to inspect metabolic activities within subcellular compartments has been a major barrier to our understanding of eukaryotic cell metabolism. Here, we describe a spatial-fluxomics approach for inferring metabolic fluxes in mitochondria and cytosol under physiological conditions, combining isotope tracing, rapid subcellular fractionation, LC-MS-based metabolomics, computational deconvolution, and metabolic network modeling. Applied to study reductive glutamine metabolism in cancer cells, shown to mediate fatty acid biosynthesis under hypoxia and defective mitochondria, we find a previously unappreciated role of reductive IDH1 as the sole net contributor of carbons to fatty acid biosynthesis under standard normoxic conditions in HeLa cells. In murine cells with defective SDH, we find that reductive biosynthesis of citrate in mitochondria is followed by a reversed CS activity, suggesting a new route for supporting pyrimidine biosynthesis. We expect this spatial-fluxomics approach to be a highly useful tool for elucidating the role of metabolic dysfunction in human disease.
    DOI:  https://doi.org/10.1038/s41467-019-09352-1
  8. Autophagy. 2019 Mar 20.
    PSEN2 (presenilin 2) mutants linked to familial Alzheimer disease impair autophagy by altering Ca2+ homeostasis.
    Chiara Fedeli, Riccardo Filadi, Alice Rossi, Cristina Mammucari, Paola Pizzo.
      PSEN2 (presenilin 2) is one of the 3 proteins that, when mutated, causes early onset familial Alzheimer disease (FAD) cases. In addition to its well-known role within the γ-secretase complex (the enzyme ultimately responsible for Aβ peptides formation), PSEN2 is endowed with some γ-secretase-independent functions in distinct cell signaling pathways, such as the modulation of intracellular Ca2+ homeostasis. Here, by using different FAD-PSEN2 cell models, we demonstrate that mutated PSEN2 impairs autophagy by causing a block in the degradative flux at the level of the autophagosome-lysosome fusion step. The defect does not depend on an altered lysosomal functionality but rather on a decreased recruitment of the small GTPase RAB7 to autophagosomes, a key event for normal autophagy progression. Importantly, FAD-PSEN2 action on autophagy is unrelated to its γ-secretase activity but depends on its previously reported ability to partially deplete ER Ca2+ content, thus reducing cytosolic Ca2+ response upon IP3-linked cell stimulations. Our data sustain the pivotal role for Ca2+ signaling in autophagy and reveal a novel mechanism by which FAD-linked presenilins alter the degradative process, reinforcing the view of a causative role for a dysfunctional quality control pathway in AD neurodegeneration.
    Keywords:  ATP2A/SERCA; Alzheimer disease; ER-mitochondria tethering; RAB7; autophagosome-lysosome fusion; calcium; presenilin
    DOI:  https://doi.org/10.1080/15548627.2019.1596489
  9. Oncogene. 2019 Mar 20.
    Mitochondrial fission-induced mtDNA stress promotes tumor-associated macrophage infiltration and HCC progression.
    Dengke Bao, Jing Zhao, Xingchun Zhou, Qi Yang, Yibing Chen, Jianjun Zhu, Peng Yuan, Jin Yang, Tao Qin, Shaogui Wan, Jinliang Xing.
      Tumor-associated macrophages (TAMs) contribute to hepatocellular carcinoma (HCC) progression. However, the molecular mechanism underlying the infiltration of TAMs into HCC microenvironment is largely unclear. Recent studies have reported that alteration of mitochondrial nucleoid structures induces mitochondrial DNA (mtDNA) release into the cytosol, which is recognized as mtDNA stress, and consequently regulates innate immunity. Here we aimed to investigate whether mitochondrial fission induces mtDNA stress and then promotes TAM infiltration and HCC progression. Confocal microscopy and real-time PCR were used to detect cytosolic mtDNA content in HCC cells. The relationship between the expression of mitochondrial fission key regulator dynamin-related protein 1 (Drp1) and the percentage of CD163 (a marker of TAMs)-positive cells was investigated in HCC tissues using immunohistochemistry. Finally, the effect of Drp1 overexpression in HCC cells on recruitment and polarization of TAMs was investigated. Our data showed that increased Drp1 expression was positively correlated with the infiltration of TAMs into HCC tissues. Drp1-mediated mitochondrial fission induced the cytosolic mtDNA stress to enhance the CCL2 secretion from HCC cells by TLR9-mediated NF-κB signaling pathway, and thus promoted the TAM recruitment and polarization. Depleting cytosolic mtDNA using DNase I or blocking TLR9 pathway by TLR9 antagonist, siRNA for TLR9 or p65 in HCC cells with Drp1 overexpression significantly decreased the recruitment and polarization of TAMs. Blocking CCR2 by antagonist significantly reduced TAM infiltration and suppressed HCC progression in mouse model. In conclusion, our findings reveal a novel mechanism of TAM infiltration in HCC by mitochondrial fission-induced mtDNA stress.
    DOI:  https://doi.org/10.1038/s41388-019-0772-z
  10. Nat Cell Biol. 2019 Mar 18.
    Mitochondrial protein-induced stress triggers a global adaptive transcriptional programme.
    Felix Boos, Lena Krämer, Carina Groh, Ferris Jung, Per Haberkant, Frank Stein, Florian Wollweber, Adrian Gackstatter, Eva Zöller, Martin van der Laan, Mikhail M Savitski, Vladimir Benes, Johannes M Herrmann.
      The cytosolic accumulation of mitochondrial precursors is hazardous to cellular fitness and is associated with a number of diseases. However, it is not observed under physiological conditions. Individual mechanisms that allow cells to avoid cytosolic accumulation of mitochondrial precursors have recently been discovered, but their interplay and regulation remain elusive. Here, we show that cells rapidly launch a global transcriptional programme to restore cellular proteostasis after induction of a 'clogger' protein that reduces the number of available mitochondrial import sites. Cells upregulate the protein folding and proteolytic systems in the cytosol and downregulate both the cytosolic translation machinery and many mitochondrial metabolic enzymes, presumably to relieve the workload of the overstrained mitochondrial import system. We show that this transcriptional remodelling is a combination of a 'wideband' core response regulated by the transcription factors Hsf1 and Rpn4 and a unique mitoprotein-induced downregulation of the oxidative phosphorylation components, mediated by an inactivation of the HAP complex.
    DOI:  https://doi.org/10.1038/s41556-019-0294-5
  11. Prog Biophys Mol Biol. 2019 Mar 14. pii: S0079-6107(18)30242-6. [Epub ahead of print]
    Cancer mutational burden is shaped by G4 DNA, replication stress and mitochondrial dysfunction.
    Albino Bacolla, Zu Ye, Zamal Ahmed, John A Tainer.
      A hallmark of cancer is genomic instability, which can enable cancer cells to evade therapeutic strategies. Here we employed a computational approach to uncover mechanisms underlying cancer mutational burden by focusing upon relationships between 1) translocation breakpoints and the thousands of G4 DNA-forming sequences within retrotransposons impacting transcription and exemplifying probable non-B DNA structures and 2) transcriptome profiling and cancer mutations. We determined the location and number of G4 DNA-forming sequences in the Genome Reference Consortium Human Build 38 and found a total of 358,605 covering ∼13.4 million bases. By analyzing >97,000 unique translocation breakpoints from the Catalogue Of Somatic Mutations In Cancer (COSMIC), we found that breakpoints are overrepresented at G4 DNA-forming sequences within hominid-specific SVA retrotransposons, and generally occur in tumors with mutations in tumor suppressor genes, such as TP53. Furthermore, correlation analyses between mRNA levels and exome mutational loads from The Cancer Genome Atlas (TCGA) encompassing >450,000 gene-mutation regressions revealed strong positive and negative associations, which depended upon tissue of origin. The strongest positive correlations originated from genes not listed as cancer genes in COSMIC; yet, these show strong predictive power for survival in most tumor types by Kaplan-Meier estimation. Thus, correlation analyses of DNA structure and gene expression with mutation loads complement and extend more traditional approaches to elucidate processes shaping genomic instability in cancer. The combined results point to G4 DNA, activation of cell cycle/DNA repair pathways, and mitochondrial dysfunction as three major factors driving the accumulation of somatic mutations in cancer cells.
    Keywords:  Cancer mutations; G-quadruplexes; Genome instability; Mitochondrial dysfunction; Replication stress; Translocation breakpoints
    DOI:  https://doi.org/10.1016/j.pbiomolbio.2019.03.004
  12. Mol Med Rep. 2019 Mar 15.
    LETM1 is required for mitochondrial homeostasis and cellular viability (Review).
    Yuwen Li, Quangdon Tran, Robin Shrestha, Longzhen Piao, Sungjin Park, Jisoo Park, Jongsun Park.
      Leucine zipper/EF‑hand‑containing transmembrane protein 1 (LETM1) has been identified as the gene responsible for Wolf‑Hirschhorn syndrome (WHS), which is characterized by intellectual disability, epilepsy, growth delay and craniofacial dysgenesis. LETM1 is a mitochondrial inner membrane protein that encodes a homolog of the yeast protein Mdm38, which is involved in mitochondrial morphology. In the present review, the importance of LETM1 in WHS and its role within the mitochondrion was explored. LETM1 governs the mitochondrion ion channel and is involved in mitochondrial respiration. Recent studies have reported that LETM1 acts as a mitochondrial Ca2+/H+ antiporter. LETM1 has also been identified as a K+/H+ exchanger, and serves a role in Mg2+ homeostasis. The function of LETM1 in mitochondria regulation is regulated by its binding partners, carboxyl‑terminal modulator protein and mitochondrial ribosomal protein L36. Therefore, we describe the remarkable role of LETM1 in mitochondrial network physiology and its function in mitochondrion‑mediated cell death. In the context of these findings, we suggest that the participation of LETM1 in tumorigenesis through the alteration of cancer metabolism should be investigated. This review provides a comprehensive description of LETM1 function, which is required for mitochondrial homeostasis and cellular viability.
    DOI:  https://doi.org/10.3892/mmr.2019.10041
  13. J Cachexia Sarcopenia Muscle. 2019 Mar 20.
    Fibroblast growth factor 21 controls mitophagy and muscle mass.
    Lynette J Oost, Monika Kustermann, Andrea Armani, Bert Blaauw, Vanina Romanello.
       BACKGROUND: Skeletal muscle is a plastic tissue that adapts to changes in exercise, nutrition, and stress by secreting myokines and myometabolites. These muscle-secreted factors have autocrine, paracrine, and endocrine effects, contributing to whole body homeostasis. Muscle dysfunction in aging sarcopenia, cancer cachexia, and diabetes is tightly correlated with the disruption of the physiological homeostasis at the whole body level. The expression levels of the myokine fibroblast growth factor 21 (FGF21) are very low in normal healthy muscles. However, fasting, ER stress, mitochondrial myopathies, and metabolic disorders induce its release from muscles. Although our understanding of the systemic effects of muscle-derived FGF21 is exponentially increasing, the direct contribution of FGF21 to muscle function has not been investigated yet.
    METHODS: Muscle-specific FGF21 knockout mice were generated to investigate the consequences of FGF21 deletion concerning skeletal muscle mass and force. To identify the mechanisms underlying FGF21-dependent adaptations in skeletal muscle during starvation, the study was performed on muscles collected from both fed and fasted adult mice. In vivo overexpression of FGF21 was performed in skeletal muscle to assess whether FGF21 is sufficient per se to induce muscle atrophy.
    RESULTS: We show that FGF21 does not contribute to muscle homeostasis in basal conditions in terms of fibre type distribution, fibre size, and muscle force. In contrast, FGF21 is required for fasting-induced muscle atrophy and weakness. The mass of isolated muscles from control-fasted mice was reduced by 15-25% (P < 0.05) compared with fed control mice. FGF21-null muscles, however, were significantly protected from muscle loss and weakness during fasting. Such important protection is due to the maintenance of protein synthesis rate in knockout muscles during fasting compared with a 70% reduction in control-fasted muscles (P < 0.01), together with a significant reduction of the mitophagy flux via the regulation of the mitochondrial protein Bnip3. The contribution of FGF21 to the atrophy programme was supported by in vivo FGF21 overexpression in muscles, which was sufficient to induce autophagy and muscle loss by 15% (P < 0.05). Bnip3 inhibition protected against FGF21-dependent muscle wasting in adult animals (P < 0.05).
    CONCLUSIONS: FGF21 is a novel player in the regulation of muscle mass that requires the mitophagy protein Bnip3.
    Keywords:  Autophagy; Bnip3; FGF21; Mitophagy; Muscle atrophy; Myokine
    DOI:  https://doi.org/10.1002/jcsm.12409
  14. Am J Physiol Lung Cell Mol Physiol. 2019 Mar 20.
    Activation of mTORC1/PGC1 axis promotes mitochondrial biogenesis and induces cellular senescence in the lung epithelium.
    Ross Summer, Hoora Shaghaghi, DeLeila Schriner, Willy Roque, Dominic Sales, Karina Cuevas-Mora, Vilas Desai, Alok Bhushan, Maria I Ramirez, Freddy Romero.
      Cellular senescence is a biological process by which cells lose their capacity to proliferate yet remain metabolically active. Although originally considered a protective mechanism to limit the formation of cancer, it is now appreciated that cellular senescence also contributes to the development of disease, including common respiratory ailments, such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. While many factors have been linked to the development of cellular senescence, mitochondrial dysfunction has emerged as an important causative factor. In this study, we uncovered that the mitochondrial biogenesis pathway driven by the mTOR/PGC1α/β axis is markedly upregulated in senescent lung epithelial cells. Using two different models, we show that activation of this pathway associates with other features characteristic of enhanced mitochondrial biogenesis, including elevated number of mitochondrion per cell, increased oxidative phosphorylation and augmented mitochondrial ROS production. Furthermore, we found that pharmacological inhibition of the mTORC1 complex with rapamycin not only restored mitochondrial homeostasis but also reduced cellular senescence to bleomycin in lung epithelial cells. Likewise, mitochondrial-specific antioxidant therapy also effectively inhibited mTORC1 activation in these cells, while concomitantly reducing mitochondrial biogenesis and cellular senescence. In summary, this study provides a mechanistic link between mitochondrial biogenesis and cellular senescence in lung epithelium and suggests that strategies aimed at blocking the mTORC1/PGC1α/β axis or reducing ROS-induced molecular damage could be effective in the treatment of senescence-associated lung diseases.
    Keywords:  , idiopathic pulmonary fibrosis; cellular senescence; lung epithelium; mammalian target of rapamycin; mitochondria
    DOI:  https://doi.org/10.1152/ajplung.00244.2018
  15. Arch Biochem Biophys. 2019 Mar 18. pii: S0003-9861(18)31001-4. [Epub ahead of print]
    Temperature dependence of mitoflash biogenesis in cardiac mitochondria.
    Peng Yu, Wenfeng Qi, Bahetiyaer Huwatibieke, Jinghang Li, Xianhua Wang, Heping Cheng.
      Mitochondrial flashes (mitoflashes) represent fundamental biochemical and biophysical dynamics of the organelle, involving sudden depolarization of mitochondrial membrane potential (ΔΨm), bursting production of reactive oxygen species (ROS), and accelerated extrusion of matrix protons. Here we investigated temperature dependence of mitoflash biogenesis as well as ΔΨm oscillations, a subset of which overlapping with mitoflashes, in both cardiac myocytes and isolated respiring cardiac mitochondria. Unexpectedly, we found that mitoflash biogenesis was essentially temperature-independent in intact cardiac myocytes, evidenced by the constancy of frequency as well as amplitude and rise speed over 5 °C-40 °C. Moderate temperature dependence was found in single mitochondria charged by respiratory substrates, where mitoflash frequency was decreased over 5 °C-20 °C with Q10 of 0.74 for Complex I substrates and 0.83 for Complex II substrate. In contrast, ΔΨm oscillation frequency displayed a negative temperature dependence at 5 °C-20 °C with Q10 of 0.82 in intact cells, but a positive temperature dependence at 25 °C - 40 °C with Q10 of 1.62 in isolated mitochondria charged with either Complex I or Complex II substrates. Moreover, the recovery speed of individual mitoflashes exhibited mild temperature dependence (Q10 = 1.14-1.22). These results suggest a temperature compensation of mitoflash frequency at both the mitochondrial and extra-organelle levels, and underscore that mitoflashes and ΔΨm oscillations are related but distinctly different mitochondrial functional dynamics.
    DOI:  https://doi.org/10.1016/j.abb.2019.03.002
  16. Autophagy. 2019 Mar 22.
    Deficiency of Mitophagy Receptor FUNDC1 Impairs Mitochondrial Quality and Aggravates Dietary-Induced Obesity and Metabolic Syndrome.
    Hao Wu, You Wang, Wenhui Li, Hui Chen, Lei Du, Dong Liu, Xiaohui Wang, Tao Xu, Lei Liu, Quan Chen.
      There is overwhelming evidence for an association between impaired mitochondrial function and metabolic syndrome. Mitophagy, a process that selectively removes damaged mitochondria via a specialized form of autophagy, is essential for mitochondrial quality control (mitochondrial QC) and metabolic homeostasis. We thus addressed the potential role of defective mitophagy in the pathogenesis of metabolic disorders. Mice lacking Fundc1, a newly characterized mitophagy receptor, develop more severe obesity and insulin resistance when fed a high-fat diet (HFD). Ablation of Fundc1 results in defective mitophagy and impaired mitochondrial QC in vitro and in white adipose tissue (WAT). In addition, there is more pronounced WAT remodeling with more adipose tissue-associated macrophages infiltration, more M1 macrophage polarization and thus an elevated inflammatory response. Mechanistically, hyperactivation of MAPK/JNK leads to insulin insensitivity, which can be inhibited by knocking out Mapk8/Jnk1 in fundc1 KO mice. Our results demonstrate that dysregulated mitochondrial QC due to defective mitophagy receptor FUNDC1 links with metabolic disorders via MAPK signaling and inflammatory responses.
    Keywords:  FUNDC1; MAPK; insulin resistance; mitochondrial QC; mitophagy; obesity
    DOI:  https://doi.org/10.1080/15548627.2019.1596482
  17. Adv Cancer Res. 2019 ;pii: S0065-230X(19)30011-9. [Epub ahead of print]142 63-105
    The second genome: Effects of the mitochondrial genome on cancer progression.
    Adam D Scheid, Thomas C Beadnell, Danny R Welch.
      The role of genetics in cancer has been recognized for centuries, but most studies elucidating genetic contributions to cancer have understandably focused on the nuclear genome. Mitochondrial contributions to cancer pathogenesis have been documented for decades, but how mitochondrial DNA (mtDNA) influences cancer progression and metastasis remains poorly understood. This lack of understanding stems from difficulty isolating the nuclear and mitochondrial genomes as experimental variables, which is critical for investigating direct mtDNA contributions to disease given extensive crosstalk exists between both genomes. Several in vitro and in vivo models have isolated mtDNA as an independent variable from the nuclear genome. This review compares and contrasts different models, their advantages and disadvantages for studying mtDNA contributions to cancer, focusing on the mitochondrial-nuclear exchange (MNX) mouse model and findings regarding tumor progression, metastasis, and other complex cancer-related phenotypes.
    Keywords:  MNX mice; Metabolism; Metastasis; Mitochondrial genetics; Polymorphism; Tumor progression
    DOI:  https://doi.org/10.1016/bs.acr.2019.01.001
  18. Autophagy. 2019 Mar 20.
    Loss of MIEF1/MiD51 confers susceptibility to BAX-mediated cell death and PINK1-PRKN-dependent mitophagy.
    Hongxu Xian, Yih-Cherng Liou.
      Mitochondrial dynamics is highly implicated in a plethora of cellular processes including apoptosis and mitophagy. However, little is known about the scope and precise functions of mitochondrial dynamics proteins for mitochondrial quality control and cellular homeostasis. Whether mitochondrial dynamics proteins serve in cellular processes reliant on mitochondrial fission-fusion is still not fully explored. MIEF1/MiD51 (mitochondrial elongation factor 1) is known to promote mitochondrial fission via the recruitment of GTPase protein DNM1L/DRP1 (dynamin 1 like), but the fundamental understandings of MIEF1 for mitochondrial-dependent cellular processes are largely elusive. Here, we report novel roles of MIEF1 in responding to apoptotic stimuli and mitochondrial damage. Given our result that staurosporine (STS) treatment induced the degradation of MIEF1 via the ubiquitin-proteasome system (UPS), we are motivated to explore the role of MIEF1 in apoptosis. MIEF1 loss triggered the imbalance of BCL2 family members on the mitochondria, consequently initiating the translocation of BAX onto the mitochondria, catalyzing the decrease of mitochondrial membrane potential and promoting the release of DIABLO/SMAC (diablo IAP-binding mitochondrial protein) and CYCS (cytochrome c, somatic). We further demonstrate that MIEF1 deficiency impaired mitochondrial respiration and induced mitochondrial oxidative stress, sensitizing cells to PINK1-PRKN-mediated mitophagy. The recruitment of PRKN to depolarized mitochondria modulated the UPS-dependent degradation of MFN2 (mitofusin 2) and FIS1 (fission, mitochondrial 1) specifically, to further promote mitophagy. Our findings uncover a bridging role of MIEF1 integrating cell death and mitophagy, unlikely dependent on mitochondrial dynamics, implying new insights to mechanisms determining cellular fate.
    Keywords:  BAX; MIEF1; PRKN; ROS; apoptosis; mitochondria; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2019.1596494
  19. Mol Cancer Res. 2019 Mar 18. pii: molcanres.1025.2018. [Epub ahead of print]
    O-GlcNAcylation enhances double strand break repair, promotes cancer cell proliferation and prevents therapy-induced senescence in irradiated tumors.
    Elena V Efimova, Oliver K Appelbe, Natalia Ricco, Steve S-Y Lee, Yue Liu, Donald J Wolfgeher, Tamica N Collins, Amy C Flor, Aishwarya Ramamurthy, Sara Warrington, Vytautas P Bindokas, Stephen J Kron.
      The metabolic reprogramming associated with characteristic increases in glucose and glutamine metabolism common in advanced cancer is often ascribed to answering a higher demand for metabolic intermediates required for rapid tumor cell growth. Instead, recent discoveries have pointed to an alternative role for glucose and glutamine metabolites as cofactors for chromatin modifiers and other protein post-translational modification enzymes in cancer cells. Beyond epigenetic mechanisms regulating gene expression, many chromatin modifiers also modulate DNA repair, raising the question whether cancer metabolic reprogramming may mediate resistance to genotoxic therapy and genomic instability. Our prior work had implicated N-acetyl-glucosamine (GlcNAc) formation by the hexosamine biosynthetic pathway (HBP) and resulting protein O-GlcNAcylation as a common means by which increased glucose and glutamine metabolism can drive double strand break (DSB) repair and resistance to therapy-induced senescence in cancer cells. We have examined the effects of modulating O-GlcNAcylation on the DNA damage response in MCF7 human mammary carcinoma in vitro and in xenograft tumors. Proteomic profiling revealed deregulated DNA-damage response pathways in cells with altered O-GlcNAcylation. Promoting protein O-GlcNAc modification by targeting O-GlcNAcase (OGA) or simply treating animals with GlcNAc, protected tumor xenografts against radiation. In turn, suppressing protein O-GlcNAcylation by blocking O-GlcNAc transferase (OGT) activity led to delayed DSB repair, reduced cell proliferation, and increased cell senescence in vivo. Taken together, these findings confirm critical connections between cancer metabolic reprogramming, DNA damage response, and senescence and provide a rationale to evaluate agents targeting O-GlcNAcylation in patients as a means to restore tumor sensitivity to radiotherapy. Implications: Finding that the hexosamine biosynthetic pathway, via its impact on protein O-GlcNAcylation, is a key determinant of the DNA damage response in cancer provides a mechanistic link between metabolic reprogramming, genomic instability and therapeutic response and suggests novel therapeutic approaches for tumor radiosensitization.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-18-1025
  20. J Hepatol. 2019 Mar 13. pii: S0168-8278(19)30144-8. [Epub ahead of print]
    F-actin dynamics regulates mammalian organ growth and cell fate maintenance.
    Arianna Pocaterra, Giulia Santinon, Patrizia Romani, Irene Brian, Andrea Dimitracopoulos, Andrea Ghisleni, Alejandro Carnicer-Lombarte, Mattia Forcato, Paola Braghetta, Marco Montagner, Francesca Galuppini, Mariaceleste Aragona, Gianmaria Pennelli, Silvio Bicciato, Nils Gauthier, Kristian Franze, Sirio Dupont.
       BACKGROUND & AIMS: In vitro, several data indicate that cell function can be regulated by the mechanical properties of cells and of the microenvironment. Cells measure these features by developing forces via their actomyosin cytoskeleton, and respond accordingly by transducing forces into biochemical signals that instruct cell behavior. Among these, the transcriptional coactivators YAP/TAZ recently emerged as key factors mediating multiple responses to actomyosin contractility. However, whether mechanical cues regulate adult liver tissue homeostasis, and whether this occurs through YAP/TAZ, remains largely unaddressed.
    METHODS & RESULTS: Here we show that the F-actin capping protein CAPZ is a critical negative regulator of actomyosin contractility and mechanotransduction. Capzb inactivation alters stress fiber and focal adhesion dynamics leading to enhanced myosin activity, increased cellular traction forces, and increased liver stiffness. In vitro, this rescues YAP from inhibition by a small geometry; in vivo, inactivation of Capzb in the adult mouse liver induces YAP activation in parallel to the Hippo pathway, causing extensive hepatocyte proliferation and leading to striking organ overgrowth. Moreover, Capzb is required for the maintenance of the differentiated hepatocyte state, for metabolic zonation, and for gluconeogenesis. In keeping with changes in tissue mechanics, inhibition of the contractility regulator ROCK, or deletion of the Yap1 mechanotransducer, reverse the phenotypes emerging in Capzb-null livers.
    CONCLUSIONS: These results indicate a previously unrecognized role for CAPZ in tuning the mechanical properties of cells and tissues, which is required in hepatocytes for the maintenance of the differentiated hepatocyte state and to regulate organ size. More in general, it indicates for the first time a physiological role of mechanotransduction in maintaining tissue homeostasis in mammals.
    LAY SUMMARY: The mechanical properties of cells and tissues (i.e. whether they are soft or stiff) are thought to be important regulators of cell behavior. A recent advancement in our understanding of these phenomena has been the identification of YAP and TAZ as key factors mediating the biological responses of cells to mechanical signals in vitro. However, whether the mechanical properties of cells and/or the mechanical regulation of YAP/TAZ are relevant for mammalian tissue physiology remains unknown. Here we challenge this issue by genetic inactivation of CAPZ, a protein that regulates the cytoskeleton, i.e. the cells' scaffold by which they sense mechanical cues. We found that inactivation of CAPZ alters cells' and liver tissue's mechanical properties, leading to YAP hyperactivation. In turn, this profoundly alters liver physiology, causing organ overgrowth, defects in liver cell differentiation and metabolism. These results reveal a previously uncharacterized role for mechanical signals for the maintenance of adult liver homeostasis.
    Keywords:  CAPZ; Capping protein; F-actin dynamics; Gluconeogenesis; Glucose metabolism; Hepatocyte cell fate maintenance; Hippo; Liver homeostasis; Mechanotransduction; Organ growth; Xenobiotic metabolism; YAP
    DOI:  https://doi.org/10.1016/j.jhep.2019.02.022
  21. Redox Biol. 2019 Mar 10. pii: S2213-2317(19)30203-4. [Epub ahead of print]22 101165
    Mitochondria in precision medicine; linking bioenergetics and metabolomics in platelets.
    Balu K Chacko, Matthew R Smith, Michelle S Johnson, Gloria Benavides, Matilda L Culp, Jyotsna Pilli, Sruti Shiva, Karan Uppal, Young-Mi Go, Dean P Jones, Victor M Darley-Usmar.
      Mitochondria possess reserve bioenergetic capacity, supporting protection and resilience in the face of disease. Approaches are limited to understand factors that impact mitochondrial functional reserve in humans. We applied the mitochondrial stress test (MST) to platelets from healthy subjects and found correlations between energetic parameters and mitochondrial function. These parameters were not correlated with mitochondrial complex I-IV activities, however, suggesting that other factors affect mitochondrial bioenergetics and metabolism. Platelets from African American patients with sickle cell disease also differed from controls, further showing that other factors impact mitochondrial bioenergetics and metabolism. To test for correlations of platelet metabolites with energetic parameters, we performed an integrated analysis of metabolomics and MST parameters. Subsets of metabolites, including fatty acids and xenobiotics correlated with mitochondrial parameters. The results establish platelets as a platform to integrate bioenergetics and metabolism for analysis of mitochondrial function in precision medicine.
    DOI:  https://doi.org/10.1016/j.redox.2019.101165
  22. Mol Cell. 2019 Mar 09. pii: S1097-2765(19)30102-9. [Epub ahead of print]
    MDM2 Integrates Cellular Respiration and Apoptotic Signaling through NDUFS1 and the Mitochondrial Network.
    Rana Elkholi, Ioana Abraham-Enachescu, Andrew P Trotta, Camila Rubio-Patiño, Jarvier N Mohammed, Mark P A Luna-Vargas, Jesse D Gelles, Joshua R Kaminetsky, Madhavika N Serasinghe, Cindy Zou, Sumaira Ali, Gavin P McStay, Cathie M Pfleger, Jerry Edward Chipuk.
      Signaling diversity and subsequent complexity in higher eukaryotes is partially explained by one gene encoding a polypeptide with multiple biochemical functions in different cellular contexts. For example, mouse double minute 2 (MDM2) is functionally characterized as both an oncogene and a tumor suppressor, yet this dual classification confounds the cell biology and clinical literatures. Identified via complementary biochemical, organellar, and cellular approaches, we report that MDM2 negatively regulates NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1), leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis. MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial localization and ultimately causing complex I and supercomplex destabilization and inefficiency of oxidative phosphorylation. The MDM2 amino-terminal region is sufficient to bind NDUFS1, alter supercomplex assembly, and induce apoptosis. Finally, this pathway is independent of p53, and several mitochondrial phenotypes are observed in Drosophila and murine models expressing transgenic Mdm2.
    Keywords:  BCL-2 family; MDM2; NDUFS1; apoptosis; complex I; mitochondria
    DOI:  https://doi.org/10.1016/j.molcel.2019.02.012
  23. Sci Rep. 2019 Mar 19. 9(1): 4844
    Dysregulated Redox Regulation Contributes to Nuclear EGFR Localization and Pathogenicity in Lung Cancer.
    Andrew C Little, Milena Hristova, Loes van Lith, Caspar Schiffers, Christopher M Dustin, Aida Habibovic, Karamatullah Danyal, David E Heppner, Miao-Chong J Lin, Jos van der Velden, Yvonne M Janssen-Heininger, Albert van der Vliet.
      Lung cancers are frequently characterized by inappropriate activation of epidermal growth factor receptor (EGFR)-dependent signaling and epigenetic silencing of the NADPH oxidase (NOX) enzyme DUOX1, both potentially contributing to worse prognosis. Based on previous findings linking DUOX1 with redox-dependent EGFR activation, the present studies were designed to evaluate whether DUOX1 silencing in lung cancers may be responsible for altered EGFR regulation. In contrast to normal epithelial cells, EGF stimulation of lung cancer cell lines that lack DUOX1 promotes EGF-induced EGFR internalization and nuclear localization, associated with induction of EGFR-regulated genes and related tumorigenic outcomes. Each of these outcomes could be reversed by overexpression of DUOX1 or enhanced by shRNA-dependent DUOX1 silencing. EGF-induced nuclear EGFR localization in DUOX1-deficient lung cancer cells was associated with altered dynamics of cysteine oxidation of EGFR, and an overall reduction of EGFR cysteines. These various outcomes could also be attenuated by silencing of glutathione S-transferase P1 (GSTP1), a mediator of metabolic alterations and drug resistance in various cancers, and a regulator of cysteine oxidation. Collectively, our findings indicate DUOX1 deficiency in lung cancers promotes dysregulated EGFR signaling and enhanced GSTP1-mediated turnover of EGFR cysteine oxidation, which result in enhanced nuclear EGFR localization and tumorigenic properties.
    DOI:  https://doi.org/10.1038/s41598-019-41395-8
  24. J Immunol. 2019 Mar 18. pii: ji1801627. [Epub ahead of print]
    Dimethyl Fumarate Disrupts Human Innate Immune Signaling by Targeting the IRAK4-MyD88 Complex.
    Balyn W Zaro, Ekaterina V Vinogradova, Daniel C Lazar, Megan M Blewett, Radu M Suciu, Junichiro Takaya, Sean Studer, Juan Carlos de la Torre, Jean-Laurent Casanova, Benjamin F Cravatt, John R Teijaro.
      Dimethyl fumarate (DMF) is a prescribed treatment for multiple sclerosis and has also been used to treat psoriasis. The electrophilicity of DMF suggests that its immunosuppressive activity is related to the covalent modification of cysteine residues in the human proteome. Nonetheless, our understanding of the proteins modified by DMF in human immune cells and the functional consequences of these reactions remains incomplete. In this study, we report that DMF inhibits human plasmacytoid dendritic cell function through a mechanism of action that is independent of the major electrophile sensor NRF2. Using chemical proteomics, we instead identify cysteine 13 of the innate immune kinase IRAK4 as a principal cellular target of DMF. We show that DMF blocks IRAK4-MyD88 interactions and IRAK4-mediated cytokine production in a cysteine 13-dependent manner. Our studies thus identify a proteomic hotspot for DMF action that constitutes a druggable protein-protein interface crucial for initiating innate immune responses.
    DOI:  https://doi.org/10.4049/jimmunol.1801627
  25. J Biol Chem. 2019 Mar 18. pii: jbc.RA118.006506. [Epub ahead of print]
    The plant triterpenoid celastrol blocks PINK1-dependent mitophagy by disrupting PINK1's association with the mitochondrial protein TOM20.
    Conggang Zhang, Rongchun Wang, Zeyu Liu, Eric Bunker, Schuyler Lee, Michelle Giuntini, Douglas Chapnick, Xuedong Liu.
      A critical function of the PTEN-induced kinase 1 (PINK1)-parkin pathway is to mediate the clearing of unhealthy or damaged mitochondria via mitophagy. Loss of either PINK1 or Parkin protein expression is associated with Parkinson's disease. Here, using a high-throughput screening approach, along with recombinant protein expression and kinase, immunoblotting, and immunofluorescence live-cell imaging assays, we report that celastrol, a pentacyclic triterpenoid isolated from extracts of the medicinal plant Tripterygium wilfordii, blocks recruitment of Parkin to mitochondria, preventing mitophagy in response to mitochondrial depolarization induced by carbonyl cyanide m-chlorophenyl hydrazone (CCCP) or to gamitrinib-induced inhibition of mitochondrial heat shock protein 90 (HSP90). Celastrol's effect on mitophagy was independent of its known role in microtubule disruption. Instead, we show that celastrol suppresses Parkin recruitment by inactivating PINK1 and preventing it from phosphorylating Parkin and also ubiquitin. We also observed that PINK1 directly and strongly associates with TOM20, a component of the translocase of outer mitochondrial membrane (TOM) machinery and relatively weak binding to another TOM subunit, TOM70. Moreover, celastrol disrupted binding between PINK1 and TOM20 both in vitro and in vivo, but did not affect binding between TOM20 and TOM70. Using native gel analysis, we also show that celastrol disrupts PINK1 complex formation upon mitochondrial depolarization and sequesters PINK1 to high-molecular-weight protein aggregates. These results reveal that celastrol regulates the mitochondrial quality control pathway by interfering with PINK1-TOM20 binding.
    Keywords:  Celastrol; Gamitrinib; PTEN-induced putative kinase 1 (PINK1); TOM20; TOM70; chemical biology; mitochondria; mitophagy; parkin; plant terpenoid
    DOI:  https://doi.org/10.1074/jbc.RA118.006506
  26. Can J Physiol Pharmacol. 2019 Mar 20.
    Developmental and sex differences in cardiac tolerance to ischemia/reperfusion injury: the role of mitochondria.
    Bohuslav Ostadal, Zdenek Drahota, Josef Houstek, Marie Milerova, Ivana Ostadalova, Marketa Hlavackova, Frantisek Kolar.
      Age and sex play essential role in the cardiac tolerance to ischemia/reperfusion (I/R) injury: cardiac resistance significantly decreases during postnatal maturation and female heart is more tolerant as compared with the male myocardium. It is widely accepted that mitochondrial dysfunction and particularly mitochondrial permeability transition pore (MPTP) opening plays a major role in determining the extent of cardiac I/R injury. We have observed that the MPTP sensitivity to the calcium load differs in mitochondria isolated from neonatal and adult myocardium as well as from adult male and female hearts. Neonatal and female mitochondria are more resistant both in the extent and in the rate of mitochondrial swelling induced by high calcium concentration. Our data further suggest that age- and sex-dependent specificity of the MPTP is not the result of different amounts of ATP synthase and cyclophilin D (CypD): neonatal and adult hearts, similarly as the male and female hearts contain comparable amount of MPTP and its regulatory protein CypD. We can speculate that the lower sensitivity of MPTP to the calcium induced swelling may be related to the higher ischemic tolerance of both neonatal and female myocardium.
    DOI:  https://doi.org/10.1139/cjpp-2019-0060
  27. Cell Death Discov. 2019 ;5 76
    Low-dose 2-deoxyglucose and metformin synergically inhibit proliferation of human polycystic kidney cells by modulating glucose metabolism.
    Jing Zhao, Yuxiang Ma, Yingjie Zhang, Bo Fu, Xiaoyuan Wu, Qinggang Li, Guangyan Cai, Xiangmei Chen, Xue-Yuan Bai.
      Polycystic kidney disease (PKD) is a common hereditary kidney disease with abnormal proliferation and apoptosis of kidney cystic epithelial cells, eventually leading to chronic renal failure. Currently, there are no effective treatment methods. Similar to tumor cells, cystic epithelial cells have abnormal glycolysis and over-activation of proliferation signaling pathways. In the present study, for the first time, we investigated the effects of low-dose combinational use of 2-deoxyglucose (2-DG) and metformin (MET) on the proliferation and apoptosis in the human cystic kidney epithelial cells. Cystic epithelia cells were divided into control group, 2-DG group, MET group and 2-DG+MET group. Cell Proliferation, apoptosis and glucose metabolism were measured in each group. The results showed that low-dose combinational treatment of 2-DG and MET significantly inhibited the proliferation of renal cystic epithelial cells by suppressing the activities of PKA, mTOR and ERK signaling pathways and upregulating PI3K/Akt pathway. Combination of both drugs increased the apoptosis rates of cystic epithelial cells. Two drugs inhibited glucose metabolic phenotypes, glycolysis and oxidative phosphorylation, and significantly lowered the intracellular ATP level in cystic epithelial cells. 2-DG could also neutralize excessive production of lactate (lactic acidosis) caused by MET and both drugs had complementary effect for cystic epithelial cells. These results reveal that combinational use of low-dose 2-DG and MET can markedly inhibit proliferation via modulating glucose metabolic phenotypes in human polycystic kidney epithelial cells, low-dose combinational use of both drugs can also lower the toxic effects of each drug, and is a novel strategy for future treatment of human polycystic kidney disease.
    DOI:  https://doi.org/10.1038/s41420-019-0156-8
  28. Oncogene. 2019 Mar 20.
    ROR1-CAVIN3 interaction required for caveolae-dependent endocytosis and pro-survival signaling in lung adenocarcinoma.
    Tomoya Yamaguchi, Miyu Hayashi, Lisa Ida, Masatoshi Yamamoto, Can Lu, Taisuke Kajino, Jinglei Cheng, Masahiro Nakatochi, Hisanori Isomura, Masaya Yamazaki, Motoshi Suzuki, Toyoshi Fujimoto, Takashi Takahashi.
      The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transcriptional target of the lineage-survival oncogene NKX2-1/TTF-1 in lung adenocarcinomas. In addition to its kinase-dependent role, ROR1 functions as a scaffold protein to facilitate interaction between caveolin-1 (CAV1) and CAVIN1, and consequently maintains caveolae formation, which in turn sustains pro-survival signaling toward AKT from multiple receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR), MET (proto-oncogene, receptor tyrosine kinase), and IGF-IR (insulin-like growth factor receptor 1). Therefore, ROR1 is an attractive target for overcoming EGFR-TKI resistance due to various mechanisms such as EGFR T790M double mutation and bypass signaling from other RTKs. Here, we report that ROR1 possesses a novel scaffold function indispensable for efficient caveolae-dependent endocytosis. CAVIN3 was found to bind with ROR1 at a site distinct from sites for CAV1 and CAVIN1, a novel function required for proper CAVIN3 subcellular localization and caveolae-dependent endocytosis, but not caveolae formation itself. Furthermore, evidence of a mechanistic link between ROR1-CAVIN3 interaction and consequential caveolae trafficking, which was found to utilize a binding site distinct from those for ROR1 interactions with CAV1 and CAVIN1, with RTK-mediated pro-survival signaling towards AKT in early endosomes in lung adenocarcinoma cells was also obtained. The present findings warrant future study to enable development of novel therapeutic strategies for inhibiting the multifaceted scaffold functions of ROR1 in order to reduce the intolerable death toll from this devastating cancer.
    DOI:  https://doi.org/10.1038/s41388-019-0785-7
  29. Open Biol. 2019 Mar 29. 9(3): 180267
    A battle for transmission: the cooperative and selfish animal mitochondrial genomes.
    Anna Klucnika, Hansong Ma.
      The mitochondrial genome is an evolutionarily persistent and cooperative component of metazoan cells that contributes to energy production and many other cellular processes. Despite sharing the same host as the nuclear genome, the multi-copy mitochondrial DNA (mtDNA) follows very different rules of replication and transmission, which translate into differences in the patterns of selection. On one hand, mtDNA is dependent on the host for its transmission, so selections would favour genomes that boost organismal fitness. On the other hand, genetic heterogeneity within an individual allows different mitochondrial genomes to compete for transmission. This intra-organismal competition could select for the best replicator, which does not necessarily give the fittest organisms, resulting in mito-nuclear conflict. In this review, we discuss the recent advances in our understanding of the mechanisms and opposing forces governing mtDNA transmission and selection in bilaterians, and what the implications of these are for mtDNA evolution and mitochondrial replacement therapy.
    Keywords:  heteroplasmy; mitochondrial DNA; mitochondrial replacement therapy; purifying selection; selfish selection
    DOI:  https://doi.org/10.1098/rsob.180267
  30. Nat Commun. 2019 Mar 20. 10(1): 1287
    Coming together to define membrane contact sites.
    Luca Scorrano, Maria Antonietta De Matteis, Scott Emr, Francesca Giordano, György Hajnóczky, Benoît Kornmann, Laura L Lackner, Tim P Levine, Luca Pellegrini, Karin Reinisch, Rosario Rizzuto, Thomas Simmen, Harald Stenmark, Christian Ungermann, Maya Schuldiner.
      Close proximities between organelles have been described for decades. However, only recently a specific field dealing with organelle communication at membrane contact sites has gained wide acceptance, attracting scientists from multiple areas of cell biology. The diversity of approaches warrants a unified vocabulary for the field. Such definitions would facilitate laying the foundations of this field, streamlining communication and resolving semantic controversies. This opinion, written by a panel of experts in the field, aims to provide this burgeoning area with guidelines for the experimental definition and analysis of contact sites. It also includes suggestions on how to operationally and tractably measure and analyze them with the hope of ultimately facilitating knowledge production and dissemination within and outside the field of contact-site research.
    DOI:  https://doi.org/10.1038/s41467-019-09253-3
  31. J Clin Invest. 2019 Mar 18. pii: 124194. [Epub ahead of print]130
    Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A model.
    Yueqin Zhou, Sharon Carmona, A K M G Muhammad, Shaughn Bell, Jesse Landeros, Michael Vazquez, Ritchie Ho, Antonietta Franco, Bin Lu, Gerald W Dorn, Shaomei Wang, Cathleen M Lutz, Robert H Baloh.
      Mitofusin-2 (MFN2) is a mitochondrial outer-membrane protein that plays a pivotal role in mitochondrial dynamics in most tissues, yet mutations in MFN2, which cause Charcot-Marie-Tooth disease type 2A (CMT2A), primarily affect the nervous system. We generated a transgenic mouse model of CMT2A that developed severe early onset vision loss and neurological deficits, axonal degeneration without cell body loss, and cytoplasmic and axonal accumulations of fragmented mitochondria. While mitochondrial aggregates were labeled for mitophagy, mutant MFN2 did not inhibit Parkin-mediated degradation, but instead had a dominant negative effect on mitochondrial fusion only when MFN1 was at low levels, as occurs in neurons. Finally, using a transgenic approach, we found that augmenting the level of MFN1 in the nervous system in vivo rescued all phenotypes in mutant MFN2R94Q-expressing mice. These data demonstrate that the MFN1/MFN2 ratio is a key determinant of tissue specificity in CMT2A and indicate that augmentation of MFN1 in the nervous system is a viable therapeutic strategy for the disease.
    Keywords:  Mouse models; Neurodegeneration; Neuromuscular disease; Neuroscience
    DOI:  https://doi.org/10.1172/JCI124194
  32. Cell Rep. 2019 Mar 19. pii: S2211-1247(19)30267-0. [Epub ahead of print]26(12): 3429-3443.e3
    Multi-dimensional Transcriptional Remodeling by Physiological Insulin In Vivo.
    Thiago M Batista, Ruben Garcia-Martin, Weikang Cai, Masahiro Konishi, Brian T O'Neill, Masaji Sakaguchi, Jong Hun Kim, Dae Young Jung, Jason K Kim, C Ronald Kahn.
      Regulation of gene expression is an important aspect of insulin action but in vivo is intertwined with changing levels of glucose and counter-regulatory hormones. Here we demonstrate that under euglycemic clamp conditions, physiological levels of insulin regulate interrelated networks of more than 1,000 transcripts in muscle and liver. These include expected pathways related to glucose and lipid utilization, mitochondrial function, and autophagy, as well as unexpected pathways, such as chromatin remodeling, mRNA splicing, and Notch signaling. These acutely regulated pathways extend beyond those dysregulated in mice with chronic insulin deficiency or insulin resistance and involve a broad network of transcription factors. More than 150 non-coding RNAs were regulated by insulin, many of which also responded to fasting and refeeding. Pathway analysis and RNAi knockdown revealed a role for lncRNA Gm15441 in regulating fatty acid oxidation in hepatocytes. Altogether, these changes in coding and non-coding RNAs provide an integrated transcriptional network underlying the complexity of insulin action.
    Keywords:  diabetes; fatty acid oxidation; gene expression; insulin action; liver; mitochondria; non-coding RNAs; skeletal muscle
    DOI:  https://doi.org/10.1016/j.celrep.2019.02.081
  33. Cell Calcium. 2019 Feb 16. pii: S0143-4160(17)30196-3. [Epub ahead of print]79 89-97
    Redox regulation of ER and mitochondrial Ca2+ signaling in cell survival and death.
    Suresh K Joseph, David M Booth, Michael P Young, György Hajnóczky.
      Physiological signaling by reactive oxygen species (ROS) and their pathophysiological role in cell death are well recognized. This review focuses on two ROS targets that are key to local Ca2+ signaling at the ER/mitochondrial interface - notably, inositol trisphosphate receptors (IP3Rs) and the mitochondrial calcium uniporter (MCU). Both transport systems are central to molecular mechanisms in cell survival and death. Methods for the measurement of the redox state of these proteins and for the detection of ROS nanodomains are described. Recent results on the redox regulation of these proteins are reviewed.
    Keywords:  Ca(2+); IP(3); IP(3) receptor; Mitochondrial calcium uniporter; Reactive oxygen species; Redox regulation
    DOI:  https://doi.org/10.1016/j.ceca.2019.02.006
  34. J Gerontol A Biol Sci Med Sci. 2019 Mar 01. pii: glz059. [Epub ahead of print]
    mTOR signaling in mouse models of accelerated aging.
    Jin Young Lee, Brian K Kennedy, Chen-Yu Liao.
      The mechanistic target of rapamycin (mTOR) is an essential nutrient-sensing kinase that integrates and regulates a number of fundamental cellular processes required for cell growth, cell motility, translation, metabolism and autophagy. mTOR signaling has been implicated in the progression of many human diseases and its dysregulation has been reported in several pathological processes, especially in age-related human diseases and mouse models of accelerated aging. In addition, many studies have demonstrated that regulation of mTOR activity has a beneficial effect on longevity in several mouse models of aging. However, not all mouse models of accelerated aging show positive effects on aging-associated phenotypes in response to targeting mTOR signaling. Here, we review the effects of interventions that modulate mTOR signaling on aging-related phenotypes in different mouse models of accelerated aging and discuss their implications with respect to aging and aging-related disorders.
    Keywords:  age-associated disease; dietary restriction; mTORC1; mice; rapamycin
    DOI:  https://doi.org/10.1093/gerona/glz059
  35. FASEB J. 2019 Mar 20. fj201802799R
    PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia.
    Fabrizio Pin, Leah J Novinger, Joshua R Huot, Robert A Harris, Marion E Couch, Thomas M O'Connell, Andrea Bonetto.
      Cachexia is frequently accompanied by severe metabolic derangements, although the mechanisms responsible for this debilitating condition remain unclear. Pyruvate dehydrogenase kinase (PDK)4, a critical regulator of cellular energetic metabolism, was found elevated in experimental models of cancer, starvation, diabetes, and sepsis. Here we aimed to investigate the link between PDK4 and the changes in muscle size in cancer cachexia. High PDK4 and abnormal energetic metabolism were found in the skeletal muscle of colon-26 tumor hosts, as well as in mice fed a diet enriched in Pirinixic acid, previously shown to increase PDK4 levels. Viral-mediated PDK4 overexpression in myotube cultures was sufficient to promote myofiber shrinkage, consistent with enhanced protein catabolism and mitochondrial abnormalities. On the contrary, blockade of PDK4 was sufficient to restore myotube size in C2C12 cultures exposed to tumor media. Our data support, for the first time, a direct role for PDK4 in promoting cancer-associated muscle metabolic alterations and skeletal muscle atrophy.-Pin, F., Novinger, L. J., Huot, J. R., Harris, R. A., Couch, M. E., O'Connell, T. M., Bonetto, A. PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia.
    Keywords:  C2C12 myotubes; chemotherapy; energy metabolism; mitochondria; skeletal muscle atrophy
    DOI:  https://doi.org/10.1096/fj.201802799R
  36. Nat Cell Biol. 2019 Mar 18.
    A nuclear phosphoinositide kinase complex regulates p53.
    Suyong Choi, Mo Chen, Vincent L Cryns, Richard A Anderson.
      The tumour suppressor p53 (encoded by TP53) protects the genome against cellular stress and is frequently mutated in cancer. Mutant p53 acquires gain-of-function oncogenic activities that are dependent on its enhanced stability. However, the mechanisms by which nuclear p53 is stabilized are poorly understood. Here, we demonstrate that the stability of stress-induced wild-type and mutant p53 is regulated by the type I phosphatidylinositol phosphate kinase (PIPKI-α (also known as PIP5K1A)) and its product phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2). Nuclear PIPKI-α binds to p53 upon stress, resulting in the production and association of PtdIns(4,5)P2 with p53. PtdIns(4,5)P2 binding promotes the interaction between p53 and the small heat shock proteins HSP27 (also known as HSPB1) and αB-crystallin (also known as HSPB5), which stabilize nuclear p53. Moreover, inhibition of PIPKI-α or PtdIns(4,5)P2 association results in p53 destabilization. Our results point to a previously unrecognized role of nuclear phosphoinositide signalling in regulating p53 stability and implicate this pathway as a promising therapeutic target in cancer.
    DOI:  https://doi.org/10.1038/s41556-019-0297-2
  37. Curr Opin Chem Biol. 2019 Mar 15. pii: S1367-5931(19)30002-X. [Epub ahead of print]51 30-39
    Epigenetic regulation by endogenous metabolite pharmacology.
    Rhushikesh A Kulkarni, David C Montgomery, Jordan L Meier.
      Altered metabolite levels can drive epigenetic changes critical to development and disease. However, in many cases the specific protein-metabolite interactions that underlie this process remain enigmatic. In this review, we make the case that this fundamental missing information may be discovered by applying the tools of modern drug target validation to study endogenous metabolite pharmacology. We detail examples in which chemical proteomics has been applied to gain new insights into reversible and covalent metabolite signaling mechanisms, using acetyl-CoA and fumarate as case studies. Finally, we provide a brief survey of nascent chemical biology methods whose application to the study of endogenous metabolite pharmacology may further advance the field.
    DOI:  https://doi.org/10.1016/j.cbpa.2019.02.002
  38. Proc Natl Acad Sci U S A. 2019 Mar 20. pii: 201812410. [Epub ahead of print]
    Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion.
    Irmina A Elliott, Amanda M Dann, Shili Xu, Stephanie S Kim, Evan R Abt, Woosuk Kim, Soumya Poddar, Alexandra Moore, Lei Zhou, Jennifer L Williams, Joseph R Capri, Razmik Ghukasyan, Cynthia Matsumura, D Andrew Tucker, Wesley R Armstrong, Anthony E Cabebe, Nanping Wu, Luyi Li, Thuc M Le, Caius G Radu, Timothy R Donahue.
      Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors.
    Keywords:  autophagy; lysosome; nucleotide metabolism; pancreatic cancer; replication stress
    DOI:  https://doi.org/10.1073/pnas.1812410116
  39. Mol Biol Cell. 2019 Mar 20. mbcE19010046
    Mitochondrial carrier protein overloading and misfolding induce aggresomes and proteostatic adaptations in the cytosol.
    Yaxin Liu, Xiaowen Wang, Liam P Coyne, Yuan Yang, Yue Qi, Frank A Middleton, Xin Jie Chen.
      Studies in yeast showed that mitochondrial stressors not directly targeting the protein import machinery can cause mitochondrial Precursor Overaccumulation Stress (mPOS) in the cytosol independent of bioenergetics. Here, we demonstrate mPOS and stress responses in human cells. We show that overloading of mitochondrial membrane carriers, but not matrix proteins, is sufficient to induce cytosolic aggresomes and apoptosis. The aggresomes appear to triage unimported mitochondrial proteins. Interestingly, expression of highly unstable mutant variants of the mitochondrial carrier protein, Ant1, also induces aggresomes despite a >20-fold reduction in protein level compared to wild type. Thus, protein overloading, rather than accumulation, is critical for aggresome induction. The data suggests that the import of mitochondrial proteins is saturable and that the cytosol is limited in degrading unimported mitochondrial proteins. In addition, we found that EGR1, eEF1A1 and ubiquitin C are upregulated by Ant1 overloading. These proteins are known to promote autophagy, protein targeting to aggresomes and the processing of protein aggregates respectively. Finally, we found that overexpression of the misfolded variants of Ant1 induces additional cytosolic responses including proteasomal activation. In summary, our work captured a profound effect of unimported mitochondrial carrier proteins on cytosolic proteostasis and revealed multiple anti-mPOS mechanisms in human cells.
    DOI:  https://doi.org/10.1091/mbc.E19-01-0046
  40. Cell Rep. 2019 Mar 19. pii: S2211-1247(19)30252-9. [Epub ahead of print]26(12): 3212-3220.e4
    Entosis Controls a Developmental Cell Clearance in C. elegans.
    Yongchan Lee, Jens C Hamann, Mark Pellegrino, Joanne Durgan, Marie-Charlotte Domart, Lucy M Collinson, Cole M Haynes, Oliver Florey, Michael Overholtzer.
      Metazoan cell death mechanisms are diverse and include numerous non-apoptotic programs. One program called entosis involves the invasion of live cells into their neighbors and is known to occur in cancers. Here, we identify a developmental function for entosis: to clear the male-specific linker cell in C. elegans. The linker cell leads migration to shape the gonad and is removed to facilitate fusion of the gonad to the cloaca. We find that the linker cell is cleared in a manner involving cell-cell adhesions and cell-autonomous control of uptake through linker cell actin. Linker cell entosis generates a lobe structure that is deposited at the site of gonad-to-cloaca fusion and is removed during mating. Inhibition of lobe scission inhibits linker cell death, demonstrating that the linker cell invades its host while alive. Our findings demonstrate a developmental function for entosis: to eliminate a migrating cell and facilitate gonad-to-cloaca fusion, which is required for fertility.
    Keywords:  cell adhesion; cell cannibalism; engulfment; entosis; entotic cell death; gonad; linker cell death; lobe; scission; uropod
    DOI:  https://doi.org/10.1016/j.celrep.2019.02.073
  41. Neurochem Res. 2019 Mar 22.
    Succinylation Links Metabolism to Protein Functions.
    Yun Yang, Gary E Gibson.
      Post-translational modifications (PTMs) are important regulators of protein function, and integrate metabolism with physiological and pathological processes. Phosphorylation and acetylation are particularly well studied PTMs. A relatively recently discovered novel PTM is succinylation in which metabolically derived succinyl CoA modifies protein lysine groups. Succinylation causes a protein charge flip from positive to negative and a relatively large increase in mass compared to other PTMs. Hundreds of protein succinylation sites are present in proteins of multiple tissues and species, and the significance is being actively investigated. The few completed studies demonstrate that succinylation alters rates of enzymes and pathways, especially mitochondrial metabolic pathways. Thus, succinylation provides an elegant and efficient mechanism to coordinate metabolism and signaling by utilizing metabolic intermediates as sensors to regulate metabolism. Even though the brain is one of the most metabolically active organs, an understanding of the role succinylation in the nervous system is largely unknown. Data from other tissues and other PTMs suggest that succinylation provides a coupling between metabolism and protein function in the nervous system and in neurological diseases. This review provides a new insight into metabolism in neurological diseases and suggests that the drug development for these diseases requires a better understanding of succinylation and de-succinylation in the brain and other tissues.
    Keywords:  Metabolism; Mitochondria; Sirtuins; Succinlyation
    DOI:  https://doi.org/10.1007/s11064-019-02780-x
  42. Nat Commun. 2019 Mar 21. 10(1): 1296
    Targeting glutamine-addiction and overcoming CDK4/6 inhibitor resistance in human esophageal squamous cell carcinoma.
    Shuo Qie, Akihiro Yoshida, Stuart Parnham, Natalia Oleinik, Gyda C Beeson, Craig C Beeson, Besim Ogretmen, Adam J Bass, Kwok-Kin Wong, Anil K Rustgi, J Alan Diehl.
      The dysregulation of Fbxo4-cyclin D1 axis occurs at high frequency in esophageal squamous cell carcinoma (ESCC), where it promotes ESCC development and progression. However, defining a therapeutic vulnerability that results from this dysregulation has remained elusive. Here we demonstrate that Rb and mTORC1 contribute to Gln-addiction upon the dysregulation of the Fbxo4-cyclin D1 axis, which leads to the reprogramming of cellular metabolism. This reprogramming is characterized by reduced energy production and increased sensitivity of ESCC cells to combined treatment with CB-839 (glutaminase 1 inhibitor) plus metformin/phenformin. Of additional importance, this combined treatment has potent efficacy in ESCC cells with acquired resistance to CDK4/6 inhibitors in vitro and in xenograft tumors. Our findings reveal a molecular basis for cancer therapy through targeting glutaminolysis and mitochondrial respiration in ESCC with dysregulated Fbxo4-cyclin D1 axis as well as cancers resistant to CDK4/6 inhibitors.
    DOI:  https://doi.org/10.1038/s41467-019-09179-w
  43. Cancer Cell. 2019 Mar 18. pii: S1535-6108(19)30109-6. [Epub ahead of print]35(3): 339-341
    Serine and Methionine Metabolism: Vulnerabilities in Lethal Prostate Cancer.
    Xia Gao, Jason W Locasale, Michael A Reid.
      Altered metabolism is a common feature of new and recurring malignancy. In this issue of Cancer Cell, Reina-Campos and colleagues report upregulation of the serine, glycine, one-carbon (SGOC) metabolic network is required for neuroendocrine prostate cancer, a castration-resistant aggressive form of the disease, and presents a targetable vulnerability.
    DOI:  https://doi.org/10.1016/j.ccell.2019.02.014
  44. Annu Rev Biochem. 2019 Mar 22.
    Structure and Mechanisms of F-Type ATP Synthases.
    Werner Kühlbrandt.
      F1Fo ATP synthases produce most of the ATP in the cell. F-type ATP synthases have been investigated for more than 50 years, but a full understanding of their molecular mechanisms has become possible only with the recent structures of complete, functionally competent complexes determined by electron cryo-microscopy (cryo-EM). High-resolution cryo-EM structures offer a wealth of unexpected new insights. The catalytic F1 head rotates with the central γ-subunit for the first part of each ATP-generating power stroke. Joint rotation is enabled by subunit δ/OSCP acting as a flexible hinge between F1 and the peripheral stalk. Subunit a conducts protons to and from the c-ring rotor through two conserved aqueous channels. The channels are separated by ∼6 Å in the hydrophobic core of Fo, resulting in a strong local field that generates torque to drive rotary catalysis in F1. The structure of the chloroplast F1Fo complex explains how ATP synthesis is turned off at night by a redox switch. Structures of mitochondrial ATP synthase dimers indicate how they shape the inner membrane cristae. The new cryo-EM structures complete our picture of the ATP synthases and reveal the unique mechanism by which they transform an electrochemical membrane potential into biologically useful chemical energy. Expected final online publication date for the Annual Review of Biochemistry Volume 88 is June 20, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-biochem-013118-110903
  45. Oxid Med Cell Longev. 2019 ;2019 4248529
    Glycine Protects against Hypoxic-Ischemic Brain Injury by Regulating Mitochondria-Mediated Autophagy via the AMPK Pathway.
    Chen-Chen Cai, Jiang-Hu Zhu, Li-Xia Ye, Yuan-Yuan Dai, Ming-Chu Fang, Ying-Ying Hu, Shu-Lin Pan, Si Chen, Pei-Jun Li, Xiao-Qin Fu, Zhen-Lang Lin.
      Hypoxic-ischemic encephalopathy (HIE) is detrimental to newborns and is associated with high mortality and poor prognosis. Thus, the primary aim of the present study was to determine whether glycine could (1) attenuate HIE injury in rats and hypoxic stress in PC12 cells and (2) downregulate mitochondria-mediated autophagy dependent on the adenosine monophosphate- (AMP-) activated protein kinase (AMPK) pathway. Experiments conducted using an in vivo HIE animal model and in vitro hypoxic stress to PC12 cells revealed that intense autophagy associated with mitochondrial function occurred during in vivo HIE injury and in vitro hypoxic stress. However, glycine treatment effectively attenuated mitochondria-mediated autophagy. Additionally, after identifying alterations in proteins within the AMPK pathway in rats and PC12 cells following glycine treatment, cyclosporin A (CsA) and 5-aminoimidazole-4-carboxamide-1-b-4-ribofuranoside (AICAR) were administered in these models and indicated that glycine protected against HIE and CoCl2 injury by downregulating mitochondria-mediated autophagy that was dependent on the AMPK pathway. Overall, glycine attenuated hypoxic-ischemic injury in neurons via reductions in mitochondria-mediated autophagy through the AMPK pathway both in vitro and in vivo.
    DOI:  https://doi.org/10.1155/2019/4248529
  46. Nature. 2019 Mar 20.
    The expanding landscape of 'oncohistone' mutations in human cancers.
    Benjamin A Nacev, Lijuan Feng, John D Bagert, Agata E Lemiesz, JianJiong Gao, Alexey A Soshnev, Ritika Kundra, Nikolaus Schultz, Tom W Muir, C David Allis.
      Mutations in epigenetic pathways are common oncogenic drivers. Histones, the fundamental substrates for chromatin-modifying and remodelling enzymes, are mutated in tumours including gliomas, sarcomas, head and neck cancers, and carcinosarcomas. Classical 'oncohistone' mutations occur in the N-terminal tail of histone H3 and affect the function of polycomb repressor complexes 1 and 2 (PRC1 and PRC2). However, the prevalence and function of histone mutations in other tumour contexts is unknown. Here we show that somatic histone mutations occur in approximately 4% (at a conservative estimate) of diverse tumour types and in crucial regions of histone proteins. Mutations occur in all four core histones, in both the N-terminal tails and globular histone fold domains, and at or near residues that contain important post-translational modifications. Many globular domain mutations are homologous to yeast mutants that abrogate the need for SWI/SNF function, occur in the key regulatory 'acidic patch' of histones H2A and H2B, or are predicted to disrupt the H2B-H4 interface. The histone mutation dataset and the hypotheses presented here on the effect of the mutations on important chromatin functions should serve as a resource and starting point for the chromatin and cancer biology fields in exploring an expanding role of histone mutations in cancer.
    DOI:  https://doi.org/10.1038/s41586-019-1038-1
  47. Nat Metab. 2019 Mar;1(3): 340-349
    AMPK activation protects against diet induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose tissue.
    Alice E Pollard, Luís Martins, Phillip J Muckett, Sanjay Khadayate, Aurélie Bornot, Maryam Clausen, Therese Admyre, Mikael Bjursell, Rebeca Fiadeiro, Laura Wilson, Chad Whilding, Vassilios N Kotiadis, Michael R Duchen, Daniel Sutton, Lucy Penfold, Alessandro Sardini, Mohammad Bohlooly-Y, David M Smith, Jon A Read, Michael A Snowden, Angela Woods, David Carling.
      
    DOI:  https://doi.org/10.1038/s42255-019-0036-9
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