bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2019‒07‒28
fifty-two papers selected by
Christian Frezza,

  1. H+ transport is an integral function of the mitochondrial ADP/ATP carrier.
  2. mTORC2 Deficiency Alters the Metabolic Profile of Conventional Dendritic Cells.
  3. Mitohormesis and metabolic health: The interplay between ROS, cAMP and sirtuins.
  4. CHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-mediated metabolism.
  5. UCP2 gene polymorphisms in obesity and diabetes, and the role of UCP2 in cancer.
  6. Upregulation of the Autophagy Adaptor p62/SQSTM1 Prolongs Health and Lifespan in Middle-Aged Drosophila.
  7. DRP-1 functions independently of mitochondrial structural perturbations to facilitate BH3 mimetic-mediated apoptosis.
  8. Activation of NIX-mediated mitophagy by an interferon regulatory factor homologue of human herpesvirus.
  9. ERAP1 promotes Hedgehog-dependent tumorigenesis by controlling USP47-mediated degradation of βTrCP.
  10. Raptinal bypasses BAX, BAK, and BOK for mitochondrial outer membrane permeabilization and intrinsic apoptosis.
  11. Mutant huntingtin disrupts mitochondrial proteostasis by interacting with TIM23.
  12. Mitochondrial DNA: Epigenetics and Environment.
  13. mTOR hyperactivation in Down Syndrome underlies deficits in autophagy induction, autophagosome formation, and mitophagy.
  14. Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila.
  15. Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling.
  16. The Metabolic Signature of Macrophage Responses.
  17. Dimethyl fumarate and monomethyl fumarate attenuate oxidative stress and mitochondrial alterations leading to oxiapoptophagy in 158N murine oligodendrocytes treated with 7β-hydroxycholesterol.
  18. Perturbation of mitochondrial bioenergetics by polycations counteracts resistance to BRAFE600 inhibition in melanoma cells.
  19. Treg Cells Promote the SREBP1-Dependent Metabolic Fitness of Tumor-Promoting Macrophages via Repression of CD8+ T Cell-Derived Interferon-γ.
  20. Mutations in the ND2 Subunit of Mitochondrial Complex I Are Sufficient to Confer Increased Tumorigenic and Metastatic Potential to Cancer Cells.
  21. p53-cyclophilin D mediates renal tubular cell apoptosis in ischemia-reperfusion-induced acute kidney injury.
  22. Inhibition of 3-phosphoglycerate dehydrogenase (PHGDH) by indole amides abrogates de novo serine synthesis in cancer cells.
  23. Quantification of Isotopologues of Amino Acids by Multiplexed Stable Isotope-Resolved Metabolomics Using Ultrahigh-Resolution Mass Spectrometry Coupled with Direct Infusion.
  24. Mitochondria Are Dynamically Transferring Between Human Neural Cells and Alexander Disease-Associated GFAP Mutations Impair the Astrocytic Transfer.
  25. Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer.
  26. An Overview of Structure, Function and Regulation of Pyruvate Kinases.
  27. Mitochondrial targets of metformin-Are they physiologically relevant?
  28. The DNA Repair Nuclease MRE11A Functions as a Mitochondrial Protector and Prevents T Cell Pyroptosis and Tissue Inflammation.
  29. Mitochondrial GCN5L1 regulates glutaminolysis, mTORC1 activity and murine liver regeneration.
  30. Suppression of Brown Adipocyte Autophagy Improves Energy Metabolism by Regulating Mitochondrial Turnover.
  31. Pptc7 is an essential phosphatase for promoting mammalian mitochondrial metabolism and biogenesis.
  32. A novel rapamycin analog is highly selective for mTORC1 in vivo.
  33. Biochemical characterization of human D-2-hydroxyglutarate dehydrogenase and two disease related variants reveals the molecular cause of D-2-hydroxyglutaric aciduria.
  34. Increased ER-mitochondria tethering promotes axon regeneration.
  35. ATP-binding cassette A1 deficiency causes cardiolipin-driven mitochondrial dysfunction in podocytes.
  36. Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase.
  37. Mitochondrial cysteinyl-tRNA synthetase is expressed via alternative transcriptional initiation regulated by energy metabolism in yeast cells.
  38. Metabolomics Analysis of Nutrient Metabolism in β-Cells.
  39. Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome.
  40. Identification of evolutionary and kinetic drivers of NAD-dependent signaling.
  41. Exercise-Induced Mitohormesis for the Maintenance of Skeletal Muscle and Healthspan Extension.
  42. Serine and 1-carbon metabolism are required for HIF-mediated protection against retinopathy of prematurity.
  43. SQSTM1/p62 promotes mitochondrial ubiquitination independently of PINK1 and PRKN/parkin in mitophagy.
  44. Both gain and loss of Nampt function promote pressure-overload-induced heart failure.
  45. L-serine: a neglected amino acid with a potential therapeutic role in diabetes.
  46. De novo synthesis of serine and glycine fuels purine nucleotide biosynthesis in human lung cancer tissues.
  47. PI3K/mTOR inhibition of IDH1 mutant glioma leads to reduced 2HG production that is associated with increased survival.
  48. Depletion of phosphatidylinositol 4-phosphate at the Golgi translocates K-Ras to mitochondria.
  49. Spatiotemporal pH Heterogeneity as a Promoter of Cancer Progression and Therapeutic Resistance.
  50. Iron regulatory protein 2 is a suppressor of mutant p53 in tumorigenesis.
  51. Regulation of antitumour CD8 T-cell immunity and checkpoint blockade immunotherapy by Neuropilin-1.
  52. Lipidomics unveils lipid dyshomeostasis and low circulating plasmalogens as biomarkers in a monogenic mitochondrial disorder.
  1. Nature. 2019 Jul;571(7766): 515-520
    H+ transport is an integral function of the mitochondrial ADP/ATP carrier.
    Ambre M Bertholet, Edward T Chouchani, Lawrence Kazak, Alessia Angelin, Andriy Fedorenko, Jonathan Z Long, Sara Vidoni, Ryan Garrity, Joonseok Cho, Naohiro Terada, Douglas C Wallace, Bruce M Spiegelman, Yuriy Kirichok.
      The mitochondrial ADP/ATP carrier (AAC) is a major transport protein of the inner mitochondrial membrane. It exchanges mitochondrial ATP for cytosolic ADP and controls cellular production of ATP. In addition, it has been proposed that AAC mediates mitochondrial uncoupling, but it has proven difficult to demonstrate this function or to elucidate its mechanisms. Here we record AAC currents directly from inner mitochondrial membranes from various mouse tissues and identify two distinct transport modes: ADP/ATP exchange and H+ transport. The AAC-mediated H+ current requires free fatty acids and resembles the H+ leak via the thermogenic uncoupling protein 1 found in brown fat. The ADP/ATP exchange via AAC negatively regulates the H+ leak, but does not completely inhibit it. This suggests that the H+ leak and mitochondrial uncoupling could be dynamically controlled by cellular ATP demand and the rate of ADP/ATP exchange. By mediating two distinct transport modes, ADP/ATP exchange and H+ leak, AAC connects coupled (ATP production) and uncoupled (thermogenesis) energy conversion in mitochondria.
    DOI:  https://doi.org/10.1038/s41586-019-1400-3
  2. Front Immunol. 2019 ;10 1451
    mTORC2 Deficiency Alters the Metabolic Profile of Conventional Dendritic Cells.
    Alicia R Watson, Helong Dai, Yawen Zheng, Ryosuke Nakano, Anastasios D Giannou, Ashley V Menk, Donna B Stolz, Greg M Delgoffe, Angus W Thomson.
      In myeloid dendritic cells (DC), deletion of the mechanistic target of rapamycin complex 2 (TORC2) results in an augmented pro-inflammatory phenotype and T cell stimulatory activity; however, the underlying mechanism has not been resolved. Here, we demonstrate that mouse bone marrow-derived TORC2-deficient myeloid DC (TORC2-/- DC) utilize an altered metabolic program, characterized by enhanced baseline glycolytic function compared to wild-type WT control (Ctrl) DC, increased dependence on glycolytic ATP production, elevated lipid content and higher viability following stimulation with LPS. In addition, TORC2-/- DC display an increased spare respiratory capacity (SRC) compared to WT Ctrl DC; this metabolic phenotype corresponds with increased mitochondrial mass and mean mitochondrial DNA copy number, and failure of TORC2-/- DC mitochondria to depolarize following LPS stimulation. Our data suggest that the enhanced metabolic activity of TORC2-/- DC may be due to compensatory TORC1 pathway activity, namely increased expression of multiple genes upstream of Akt/TORC1 activity, including the integrin alpha IIb, protein tyrosine kinase 2/focal adhesion kinase, IL-7R and Janus kinase 1(JAK1), and the activation of downstream targets of TORC1, including p70S6K, eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) and CD36 (fatty acid translocase). These enhanced TORC1 pathway activities may culminate in increased expression of the nuclear receptor peroxisome proliferator-activated receptor γ (Pparγ) that regulates fatty acid storage, and the transcription factor sterol regulatory element-binding transcription factor 1 (Srebf1). Taken together, our data suggest that TORC2 may function to restrain TORC1-driven metabolic activity and mitochondrial regulation in myeloid DC.
    Keywords:  dendritic cells; mammalian target of rapamycin complex 2; metabolism; mitochondrial regulation; mouse; rapamycin
    DOI:  https://doi.org/10.3389/fimmu.2019.01451
  3. Free Radic Biol Med. 2019 Jul 23. pii: S0891-5849(19)30608-2. [Epub ahead of print]
    Mitohormesis and metabolic health: The interplay between ROS, cAMP and sirtuins.
    Carlos Marques Palmeira, João Soeiro Teodoro, João Alves Amorim, Clemens Steegborn, David A Sinclair, Anabela Pinto Rolo.
      The key role of mitochondria in oxidative metabolism and redox homeostasis explains the link between mitochondrial dysfunction and the development of metabolic disorders. Mitochondria's highly dynamic nature, based on alterations in biogenesis, mitophagy, fusion and fission, allows adjusting sequential redox reactions of the electron transport chain (ETC) and dissipation of the membrane potential by ATP synthase, to different environmental cues. With reactive oxygen species being an inevitable by-product of oxidative phosphorylation (OXPHOS), alterations on mitochondrial oxidative rate with a consequent excessive load of reactive oxygen species have been traditionally associated with pathological conditions. However, reactive oxygen species have also been suggested as promoters of mitohormesis, a process in which low, non-cytotoxic concentrations of reactive oxygen species promote mitochondrial homeostasis. Therefore, signaling systems involved in the regulation of mitochondrial homeostasis are attractive candidates for drug development for metabolic diseases triggered by mitochondrial dysfunction. Reversible phosphorylation downstream the cyclic AMP (cAMP) signaling cascade and deacetylation mediated by sirtuins are recognized as major mitochondrial regulators.
    Keywords:  Metabolic diseases; Mitochondria; Mitohormesis; ROS; Sirtuin; cAMP
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2019.07.017
  4. Cancer Metab. 2019 ;7 7
    CHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-mediated metabolism.
    Luke W Thomas, Cinzia Esposito, Jenna M Stephen, Ana S H Costa, Christian Frezza, Thomas S Blacker, Gyorgy Szabadkai, Margaret Ashcroft.
      Background: Mitochondrial oxidative phosphorylation (OXPHOS) via the respiratory chain is required for the maintenance of tumour cell proliferation and regulation of epithelial to mesenchymal transition (EMT)-related phenotypes through mechanisms that are not fully understood. The essential mitochondrial import protein coiled-coil helix coiled-coil helix domain-containing protein 4 (CHCHD4) controls respiratory chain complex activity and oxygen consumption, and regulates the growth of tumours in vivo. In this study, we interrogate the importance of CHCHD4-regulated mitochondrial metabolism for tumour cell proliferation and EMT-related phenotypes, and elucidate key pathways involved.Results: Using in silico analyses of 967 tumour cell lines, and tumours from different cancer patient cohorts, we show that CHCHD4 expression positively correlates with OXPHOS and proliferative pathways including the mTORC1 signalling pathway. We show that CHCHD4 expression significantly correlates with the doubling time of a range of tumour cell lines, and that CHCHD4-mediated tumour cell growth and mTORC1 signalling is coupled to respiratory chain complex I (CI) activity. Using global metabolomics analysis, we show that CHCHD4 regulates amino acid metabolism, and that CHCHD4-mediated tumour cell growth is dependent on glutamine. We show that CHCHD4-mediated tumour cell growth is linked to CI-regulated mTORC1 signalling and amino acid metabolism. Finally, we show that CHCHD4 expression in tumours is inversely correlated with EMT-related gene expression, and that increased CHCHD4 expression in tumour cells modulates EMT-related phenotypes.
    Conclusions: CHCHD4 drives tumour cell growth and activates mTORC1 signalling through its control of respiratory chain mediated metabolism and complex I biology, and also regulates EMT-related phenotypes of tumour cells.
    Keywords:  Coiled-coil helix coiled-coil helix domain-containing protein 4 (CHCHD4); HIF-1α; complex I; disulfide relay system; hypoxia; mitochondria; respiratory chain; tumour growth; tumour metabolism
    DOI:  https://doi.org/10.1186/s40170-019-0200-4
  5. FEBS Lett. 2019 Jul 22.
    UCP2 gene polymorphisms in obesity and diabetes, and the role of UCP2 in cancer.
    Jinran Li, Rihua Jiang, Xianling Cong, Yunfeng Zhao.
      Mitochondria are the primary sites for ATP synthesis and free radical generation in organisms. Abnormal mitochondrial metabolism contributes to many diseases, including obesity, diabetes, and cancer. UCP2 is an ion/anion transporter located in mitochondrial inner membrane, and has a crucial role in regulating oxidative stress, cellular metabolism, cell proliferation, and cell death. polymorphisms of the UCP2 gene have been associated with diabetes and obesity, as UCP2 is involved in energy expenditure and insulin secretion. Moreover, UCP2 gene expression is often amplified in cancers, and increased UCP2 expression contributes to cancer growth, cancer metabolism, anti-apoptosis, and drug resistance. This article will summarize the latest findings of UCP2 on obesity, diabetes, and cancer. This article is protected by copyright. All rights reserved.
    Keywords:  UCP2; cancer; diabetes; mitochondria; obesity; polymorphism
    DOI:  https://doi.org/10.1002/1873-3468.13546
  6. Cell Rep. 2019 Jul 23. pii: S2211-1247(19)30850-2. [Epub ahead of print]28(4): 1029-1040.e5
    Upregulation of the Autophagy Adaptor p62/SQSTM1 Prolongs Health and Lifespan in Middle-Aged Drosophila.
    Ricardo Aparicio, Anil Rana, David W Walker.
      Autophagy, a lysosomal degradation pathway, plays crucial roles in health and disease. p62/SQSTM1 (hereafter p62) is an autophagy adaptor protein that can shuttle ubiquitinated cargo for autophagic degradation. Here, we show that upregulating the Drosophila p62 homolog ref(2)P/dp62, starting in midlife, delays the onset of pathology and prolongs healthy lifespan. Midlife induction of dp62 improves proteostasis, in aged flies, in an autophagy-dependent manner. Previous studies have reported that p62 plays a role in mediating the clearance of dysfunctional mitochondria via mitophagy. However, the causal relationships between p62 expression, mitochondrial homeostasis, and aging remain largely unexplored. We show that upregulating dp62, in midlife, promotes mitochondrial fission, facilitates mitophagy, and improves mitochondrial function in aged flies. Finally, we show that mitochondrial fission is required for the anti-aging effects of midlife dp62 induction. Our findings indicate that p62 represents a potential therapeutic target to counteract aging and prolong health in aged mammals.
    Keywords:  aging; autophagy; longevity; midlife; mitophagy; p62
    DOI:  https://doi.org/10.1016/j.celrep.2019.06.070
  7. Cell Death Discov. 2019 ;5 117
    DRP-1 functions independently of mitochondrial structural perturbations to facilitate BH3 mimetic-mediated apoptosis.
    Mateus Milani, Alison J Beckett, Aoula Al-Zebeeby, Xu Luo, Ian A Prior, Gerald M Cohen, Shankar Varadarajan.
      Maintenance of mitochondrial integrity is critical for normal cellular homoeostasis. Most cells respond to stress stimuli and undergo apoptosis by perturbing mitochondrial structure and function to release proteins, such as cytochrome c, which are essential for the execution of the intrinsic apoptotic cascade. Cancer cells evade these events by overexpressing the anti-apoptotic BCL-2 family of proteins on mitochondrial membranes. Inhibitors of the anti-apoptotic BCL-2 family proteins, also known as BH3 mimetics, antagonise the pro-survival functions of these proteins and result in rapid apoptosis. Although the precise mechanism by which BH3 mimetics induce apoptosis has been well characterised, not much is known in terms of the structural changes that occur in mitochondria during apoptosis. Using a panel of highly selective BH3 mimetics and a wide range of cell lines, we demonstrate that BH3 mimetics induce extensive mitochondrial fission, accompanied by swelling of the mitochondrial matrix and rupture of the outer mitochondrial membrane. These changes occur in a BAX/ BAK-dependent manner. Although a major mitochondrial fission GTPase, DRP-1, has been implicated in mitochondrial apoptosis, our data demonstrate that DRP-1 might function independently/downstream of BH3 mimetic-mediated mitochondrial fission to facilitate the release of cytochrome c and apoptosis. Moreover, downregulation of DRP-1 prevented cytochrome c release and apoptosis even when OPA1, a protein mediating mitochondrial fusion, was silenced. Although BH3 mimetic-mediated displacement of BAK and other BH3-only proteins from BCL-XL and MCL-1 was unaffected by DRP-1 downregulation, it prevented BAK activation significantly, thus placing DRP-1 as one of the most critical players, along with BAX and BAK, that governs BH3 mimetic-mediated cytochrome c release and apoptosis.
    Keywords:  Cell death; Organelles
    DOI:  https://doi.org/10.1038/s41420-019-0199-x
  8. Nat Commun. 2019 Jul 19. 10(1): 3203
    Activation of NIX-mediated mitophagy by an interferon regulatory factor homologue of human herpesvirus.
    Mai Tram Vo, Barbara J Smith, John Nicholas, Young Bong Choi.
      Viral control of mitochondrial quality and content has emerged as an important mechanism for counteracting the host response to virus infection. Despite the knowledge of this crucial function of some viruses, little is known about how herpesviruses regulate mitochondrial homeostasis during infection. Human herpesvirus 8 (HHV-8) is an oncogenic virus causally related to AIDS-associated malignancies. Here, we show that HHV-8-encoded viral interferon regulatory factor 1 (vIRF-1) promotes mitochondrial clearance by activating mitophagy to support virus replication. Genetic interference with vIRF-1 expression or targeting to the mitochondria inhibits HHV-8 replication-induced mitophagy and leads to an accumulation of mitochondria. Moreover, vIRF-1 binds directly to a mitophagy receptor, NIX, on the mitochondria and activates NIX-mediated mitophagy to promote mitochondrial clearance. Genetic and pharmacological interruption of vIRF-1/NIX-activated mitophagy inhibits HHV-8 productive replication. Our findings uncover an essential role of vIRF-1 in mitophagy activation and promotion of HHV-8 lytic replication via this mechanism.
    DOI:  https://doi.org/10.1038/s41467-019-11164-2
  9. Nat Commun. 2019 Jul 24. 10(1): 3304
    ERAP1 promotes Hedgehog-dependent tumorigenesis by controlling USP47-mediated degradation of βTrCP.
    Francesca Bufalieri, Paola Infante, Flavia Bernardi, Miriam Caimano, Paolo Romania, Marta Moretti, Ludovica Lospinoso Severini, Julie Talbot, Ombretta Melaiu, Mirella Tanori, Laura Di Magno, Diana Bellavia, Carlo Capalbo, Stéphanie Puget, Enrico De Smaele, Gianluca Canettieri, Daniele Guardavaccaro, Luca Busino, Angelo Peschiaroli, Simonetta Pazzaglia, Giuseppe Giannini, Gerry Melino, Franco Locatelli, Alberto Gulino, Olivier Ayrault, Doriana Fruci, Lucia Di Marcotullio.
      The Hedgehog (Hh) pathway is essential for embryonic development and tissue homeostasis. Aberrant Hh signaling may occur in a wide range of human cancers, such as medulloblastoma, the most common brain malignancy in childhood. Here, we identify endoplasmic reticulum aminopeptidase 1 (ERAP1), a key regulator of innate and adaptive antitumor immune responses, as a previously unknown player in the Hh signaling pathway. We demonstrate that ERAP1 binds the deubiquitylase enzyme USP47, displaces the USP47-associated βTrCP, the substrate-receptor subunit of the SCFβTrCP ubiquitin ligase, and promotes βTrCP degradation. These events result in the modulation of Gli transcription factors, the final effectors of the Hh pathway, and the enhancement of Hh activity. Remarkably, genetic or pharmacological inhibition of ERAP1 suppresses Hh-dependent tumor growth in vitro and in vivo. Our findings unveil an unexpected role for ERAP1 in cancer and indicate ERAP1 as a promising therapeutic target for Hh-driven tumors.
    DOI:  https://doi.org/10.1038/s41467-019-11093-0
  10. Cell Death Dis. 2019 Jul 19. 10(8): 556
    Raptinal bypasses BAX, BAK, and BOK for mitochondrial outer membrane permeabilization and intrinsic apoptosis.
    Sina Heimer, Gertrud Knoll, Klaus Schulze-Osthoff, Martin Ehrenschwender.
      Most antineoplastic chemotherapies eliminate cancer cells through activation of the mitochondria-controlled intrinsic apoptotic pathway. Therein, BAX, BAK, and/or BOK function as the essential pore-forming executioners of mitochondrial outer membrane permeabilization (MOMP). The activation threshold of BAX and BAK also correlates inversely with the required strength of an apoptotic stimulus to induce MOMP and thereby effectively determines a cell's readiness to undergo apoptosis. Consequently, the 'gatekeepers' BAX and BAK emerged as therapeutic targets, but functional or genetic loss renders BAX/BAK-targeting strategies prone to fail. Here, we show that the small molecule Raptinal overcomes this limitation by triggering cytochrome c release in a BAX/BAK/BOK-independent manner. Raptinal exerts a dual cytotoxic effect on cancer cells by rapid activation of the intrinsic apoptotic pathway and simultaneous shutdown of mitochondrial function. Together with its efficacy to eliminate cancer cells in vivo, Raptinal could be useful in difficult-to-treat cancer entities harboring defects in the intrinsic apoptosis pathway.
    DOI:  https://doi.org/10.1038/s41419-019-1790-z
  11. Proc Natl Acad Sci U S A. 2019 Jul 25. pii: 201904101. [Epub ahead of print]
    Mutant huntingtin disrupts mitochondrial proteostasis by interacting with TIM23.
    Svitlana Yablonska, Vinitha Ganesan, Lisa M Ferrando, JinHo Kim, Anna Pyzel, Oxana V Baranova, Nicolas K Khattar, Timothy M Larkin, Sergei V Baranov, Ning Chen, Colleen E Strohlein, Donté A Stevens, Xiaomin Wang, Yue-Fang Chang, Mark E Schurdak, Diane L Carlisle, Jonathan S Minden, Robert M Friedlander.
      Mutant huntingtin (mHTT), the causative protein in Huntington's disease (HD), associates with the translocase of mitochondrial inner membrane 23 (TIM23) complex, resulting in inhibition of synaptic mitochondrial protein import first detected in presymptomatic HD mice. The early timing of this event suggests that it is a relevant and direct pathophysiologic consequence of mHTT expression. We show that, of the 4 TIM23 complex proteins, mHTT specifically binds to the TIM23 subunit and that full-length wild-type huntingtin (wtHTT) and mHTT reside in the mitochondrial intermembrane space. We investigated differences in mitochondrial proteome between wtHTT and mHTT cells and found numerous proteomic disparities between mHTT and wtHTT mitochondria. We validated these data by quantitative immunoblotting in striatal cell lines and human HD brain tissue. The level of soluble matrix mitochondrial proteins imported through the TIM23 complex is lower in mHTT-expressing cell lines and brain tissues of HD patients compared with controls. In mHTT-expressing cell lines, membrane-bound TIM23-imported proteins have lower intramitochondrial levels, whereas inner membrane multispan proteins that are imported via the TIM22 pathway and proteins integrated into the outer membrane generally remain unchanged. In summary, we show that, in mitochondria, huntingtin is located in the intermembrane space, that mHTT binds with high-affinity to TIM23, and that mitochondria from mHTT-expressing cells and brain tissues of HD patients have reduced levels of nuclearly encoded proteins imported through TIM23. These data demonstrate the mechanism and biological significance of mHTT-mediated inhibition of mitochondrial protein import, a mechanism likely broadly relevant to other neurodegenerative diseases.
    Keywords:  Huntington’s disease; TIM23; mitochondria; mutant huntingtin; proteostasis
    DOI:  https://doi.org/10.1073/pnas.1904101116
  12. Environ Mol Mutagen. 2019 Jul 23.
    Mitochondrial DNA: Epigenetics and Environment.
    Nidhi Sharma, Monica Sai Pasala, Aishwarya Prakash.
      Maintenance of the mitochondrial genome is essential for proper cellular function. For this purpose, mitochondrial DNA (mtDNA) needs to be faithfully replicated, transcribed, translated, and repaired in the face of constant onslaught from endogenous and environmental agents. While only 13 polypeptides are encoded within mtDNA, the mitochondrial proteome comprises over 1500 proteins that are encoded by nuclear genes and translocated to the mitochondria for the purpose of maintaining mitochondrial function. Regulation of mtDNA and mitochondrial proteins by epigenetic changes and post-translational modifications facilitate crosstalk between the nucleus and the mitochondria and ultimately lead to the maintenance of cellular health and homeostasis. DNA methyl transferases have been identified in the mitochondria implicating that methylation occurs within this organelle; however, the extent to which mtDNA is methylated has been debated for many years. Mechanisms of demethylation within this organelle have also been postulated, but the exact mechanisms and their outcomes is still an active area of research. Mitochondrial dysfunction in the form of altered gene expression and ATP production, resulting from epigenetic changes, can lead to various conditions including aging related neurodegenerative disorders, altered metabolism, changes in circadian rhythm, and cancer. Here, we provide an overview of the epigenetic regulation of mtDNA via methylation, long and short non-coding RNAs, and post-translational modifications of nucleoid proteins (as mitochondria lack histones). We also highlight the influence of xenobiotics such as airborne environmental pollutants, contamination from heavy metals, and therapeutic drugs on mtDNA methylation. This article is protected by copyright. All rights reserved.
    Keywords:  mitochondrial epigenetics; mitochondrial post-translational modifications; mtDNA methylation; non-coding RNAs; xenobiotics
    DOI:  https://doi.org/10.1002/em.22319
  13. Cell Death Dis. 2019 Jul 22. 10(8): 563
    mTOR hyperactivation in Down Syndrome underlies deficits in autophagy induction, autophagosome formation, and mitophagy.
    Matteo Bordi, Sandipkumar Darji, Yutaka Sato, Marian Mellén, Martin J Berg, Asok Kumar, Ying Jiang, Ralph A Nixon.
      Down syndrome (DS), a complex genetic disorder caused by chromosome 21 trisomy, is associated with mitochondrial dysfunction leading to the accumulation of damaged mitochondria. Here we report that mitophagy, a form of selective autophagy activated to clear damaged mitochondria is deficient in primary human fibroblasts derived from individuals with DS leading to accumulation of damaged mitochondria with consequent increases in oxidative stress. We identified two molecular bases for this mitophagy deficiency: PINK1/PARKIN impairment and abnormal suppression of macroautophagy. First, strongly downregulated PARKIN and the mitophagic adaptor protein SQSTM1/p62 delays PINK1 activation to impair mitophagy induction after mitochondrial depolarization by CCCP or antimycin A plus oligomycin. Secondly, mTOR is strongly hyper-activated, which globally suppresses macroautophagy induction and the transcriptional expression of proteins critical for autophagosome formation such as ATG7, ATG3 and FOXO1. Notably, inhibition of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) using AZD8055 (AZD) restores autophagy flux, PARKIN/PINK initiation of mitophagy, and the clearance of damaged mitochondria by mitophagy. These results recommend mTORC1-mTORC2 inhibition as a promising candidate therapeutic strategy for Down Syndrome.
    DOI:  https://doi.org/10.1038/s41419-019-1752-5
  14. Nat Commun. 2019 Jul 23. 10(1): 3280
    Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila.
    Simonetta Andreazza, Colby L Samstag, Alvaro Sanchez-Martinez, Erika Fernandez-Vizarra, Aurora Gomez-Duran, Juliette J Lee, Roberta Tufi, Michael J Hipp, Elizabeth K Schmidt, Thomas J Nicholls, Payam A Gammage, Patrick F Chinnery, Michal Minczuk, Leo J Pallanck, Scott R Kennedy, Alexander J Whitworth.
      Somatic mutations in the mitochondrial genome (mtDNA) have been linked to multiple disease conditions and to ageing itself. In Drosophila, knock-in of a proofreading deficient mtDNA polymerase (POLG) generates high levels of somatic point mutations and also small indels, but surprisingly limited impact on organismal longevity or fitness. Here we describe a new mtDNA mutator model based on a mitochondrially-targeted cytidine deaminase, APOBEC1. mito-APOBEC1 acts as a potent mutagen which exclusively induces C:G>T:A transitions with no indels or mtDNA depletion. In these flies, the presence of multiple non-synonymous substitutions, even at modest heteroplasmy, disrupts mitochondrial function and dramatically impacts organismal fitness. A detailed analysis of the mutation profile in the POLG and mito-APOBEC1 models reveals that mutation type (quality) rather than quantity is a critical factor in impacting organismal fitness. The specificity for transition mutations and the severe phenotypes make mito-APOBEC1 an excellent mtDNA mutator model for ageing research.
    DOI:  https://doi.org/10.1038/s41467-019-10857-y
  15. Nature. 2019 Jul 24.
    Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling.
    Jiao Wu, Alexander M Minikes, Minghui Gao, Huijie Bian, Yong Li, Brent R Stockwell, Zhi-Nan Chen, Xuejun Jiang.
      Ferroptosis, a cell death process driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated in diseases such as ischaemic organ damage and cancer1,2. The enzyme glutathione peroxidase 4 (GPX4) is a central regulator of ferroptosis, and protects cells by neutralizing lipid peroxides, which are by-products of cellular metabolism. The direct inhibition of GPX4, or indirect inhibition by depletion of its substrate glutathione or the building blocks of glutathione (such as cysteine), can trigger ferroptosis3. Ferroptosis contributes to the antitumour function of several tumour suppressors such as p53, BAP1 and fumarase4-7. Counterintuitively, mesenchymal cancer cells-which are prone to metastasis, and often resistant to various treatments-are highly susceptible to ferroptosis8,9. Here we show that ferroptosis can be regulated non-cell-autonomously by cadherin-mediated intercellular interactions. In epithelial cells, such interactions mediated by E-cadherin suppress ferroptosis by activating the intracellular NF2 (also known as merlin) and Hippo signalling pathway. Antagonizing this signalling axis allows the proto-oncogenic transcriptional co-activator YAP to promote ferroptosis by upregulating several ferroptosis modulators, including ACSL4 and TFRC. This finding provides mechanistic insights into the observations that cancer cells with mesenchymal or metastatic property are highly sensitive to ferroptosis8. Notably, a similar mechanism also modulates ferroptosis in some non-epithelial cells. Finally, genetic inactivation of the tumour suppressor NF2, a frequent tumorigenic event in mesothelioma10,11, rendered cancer cells more sensitive to ferroptosis in an orthotopic mouse model of malignant mesothelioma. Our results demonstrate the role of intercellular interactions and intracellular NF2-YAP signalling in dictating ferroptotic death, and also suggest that malignant mutations in NF2-YAP signalling could predict the responsiveness of cancer cells to future ferroptosis-inducing therapies.
    DOI:  https://doi.org/10.1038/s41586-019-1426-6
  16. Front Immunol. 2019 ;10 1462
    The Metabolic Signature of Macrophage Responses.
    Antonella Viola, Fabio Munari, Ricardo Sánchez-Rodríguez, Tommaso Scolaro, Alessandra Castegna.
      Macrophages are a heterogeneous population of immune cells playing several and diverse functions in homeostatic and immune responses. The broad spectrum of macrophage functions depends on both heterogeneity and plasticity of these cells, which are highly specialized in sensing the microenvironment and modify their properties accordingly. Although it is clear that macrophage phenotypes are difficult to categorize and should be seen as plastic and adaptable, they can be simplified into two extremes: a pro-inflammatory (M1) and an anti-inflammatory/pro-resolving (M2) profile. Based on this definition, M1 macrophages are able to start and sustain inflammatory responses, secreting pro-inflammatory cytokines, activating endothelial cells, and inducing the recruitment of other immune cells into the inflamed tissue; on the other hand, M2 macrophages promote the resolution of inflammation, phagocytose apoptotic cells, drive collagen deposition, coordinate tissue integrity, and release anti-inflammatory mediators. Dramatic switches in cell metabolism accompany these phenotypic and functional changes of macrophages. In particular, M1 macrophages rely mainly on glycolysis and present two breaks on the TCA cycle that result in accumulation of itaconate (a microbicide compound) and succinate. Excess of succinate leads to Hypoxia Inducible Factor 1α (HIF1α) stabilization that, in turn, activates the transcription of glycolytic genes, thus sustaining the glycolytic metabolism of M1 macrophages. On the contrary, M2 cells are more dependent on oxidative phosphorylation (OXPHOS), their TCA cycle is intact and provides the substrates for the complexes of the electron transport chain (ETC). Moreover, pro- and anti-inflammatory macrophages are characterized by specific pathways that regulate the metabolism of lipids and amino acids and affect their responses. All these metabolic adaptations are functional to support macrophage activities as well as to sustain their polarization in specific contexts. The aim of this review is to discuss recent findings linking macrophage functions and metabolism.
    Keywords:  immune cross-talk; inflammation; macrophage; metabolic rewiring; metabolism
    DOI:  https://doi.org/10.3389/fimmu.2019.01462
  17. J Steroid Biochem Mol Biol. 2019 Jul 22. pii: S0960-0760(18)30719-2. [Epub ahead of print] 105432
    Dimethyl fumarate and monomethyl fumarate attenuate oxidative stress and mitochondrial alterations leading to oxiapoptophagy in 158N murine oligodendrocytes treated with 7β-hydroxycholesterol.
    Randa Sghaier, Thomas Nury, Valerio Leoni, Claudio Caccia, Jean-Paul Pais De Barros, Ameur Cherif, Anne Vejux, Thibault Moreau, Khalifa Lime, Mohammad Samadi, John J Mackrill, Ahmed Slaheddine Masmoudi, Gérard Lizard, Amira Zarrouk.
      Oxidative stress and mitochondrial dysfunction contribute to the pathogenesis of neurodegenerative diseases and favor lipid peroxidation, leading to increased levels of 7β-hydroxycholesterol (7β-OHC) which induces oxiapoptophagy (OXIdative stress, APOPTOsis, autoPHAGY). The cytoprotective effects of dimethylfumarate (DMF), used in the treatment of relapsing remitting multiple sclerosis and of monomethylfumarate (MMF), its main metabolite, were evaluated on murine oligodendrocytes 158 N exposed to 7β-OHC (50 μM, 24 h) with or without DMF or MMF (25 μM). The activity of 7β-OHC in the presence or absence DMF or MMF was evaluated on several parameters: cell adhesion; plasma membrane integrity measured with propidium iodide (PI), trypan blue and fluoresceine diacetate (FDA) assays; LDH activity; antioxidant enzyme activities (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)); generation of lipid peroxidation products (malondialdehyde (MDA), conjugated dienes (CDs)) and protein oxidation products (carbonylated proteins (CPs)); reactive oxygen species (ROS) overproduction conducted with DHE and DHR123. The effect on mitochondria was determined with complementary criteria: measurement of succinate dehydrogenase activity, evaluation of mitochondrial potential (ΔΨm) and mitochondrial superoxide anions (O2●-) production using DiOC6(3) and MitoSOX, respectively; quantification of mitochondrial mass with Mitotracker Red, and of cardiolipins and organic acids. The effects on mitochondrial and peroxisomal ultrastructure were determined by transmission electron microscopy. Intracellular sterol and fatty acid profiles were determined. Apoptosis and autophagy were characterized by staining with Hoechst 33342, Giemsa and acridine orange, and with antibodies raised against caspase-3 and LC3. DMF and MMF attenuate 7β-OHC-induced cytotoxicity: cell growth inhibition; decreased cell viability; mitochondrial dysfunction (decrease of succinate dehydrogenase activity, loss of ΔΨm, increase of mitochondrial O2●- production, alteration of the tricarboxilic acid (TCA) cycle, and cardiolipin content); oxidative stress induction (ROS overproduction, alteration of GPx, CAT, and SOD activities, increased levels of MDA, CDs, and CPs); changes in fatty acid and cholesterol metabolism; and cell death induction (caspase-3 cleavage, activation of LC3-I in LC3-II). Ultrastructural alterations of mitochondria and peroxisomes were prevented. These results demonstrate that DMF and MMF prevent major dysfunctions associated with neurodegenerative diseases: oxidative stress, mitochondrial dysfunction, apoptosis and autophagy.
    Keywords:  158N cells; 7β-hydroxycholesterol; Apoptosis; Autophagy; Dimethyl fumarate; Lipid profile; Mitochondria; Monomethyl fumarate; Oxiapoptophagy; Oxidative stress; Peroxisome
    DOI:  https://doi.org/10.1016/j.jsbmb.2019.105432
  18. J Control Release. 2019 Jul 23. pii: S0168-3659(19)30418-3. [Epub ahead of print]
    Perturbation of mitochondrial bioenergetics by polycations counteracts resistance to BRAFE600 inhibition in melanoma cells.
    Arnaldur Hall, Scott Maynard, Lin-Ping Wu, Joanna Maria Merchut-Maya, Robert Strauss, Seyed Moein Moghimi, Jiri Bartek.
      Acquired resistance to the oncogenic BRAFE600 inhibitor vemurafenib is a major clinical challenge in the treatment of melanoma. Vemurafenib resistance is poorly understood; however, available evidence indicates that reprogrammed mitochondrial metabolism could contribute to the resistance mechanism. Here we show that synthetic polycations, such as polyethylenimines and poly(l-lysine)s, prevent vemurafenib resistance in melanoma cells through induction of mitochondrial bioenergetic crisis. Polycations accumulate to a higher degree in hyperpolarized mitochondria (i.e. mitochondria with greater negative charge) which partly explains greater cellular uptake and mitochondrial accumulation of polycations in melanoma cells compared with epidermal melanocytes. Combined treatment of polycations and vemurafenib diminishes the metabolic flexibility of melanoma cells, making them unable to shift between glycolysis and mitochondrial oxidative phosphorylation according to energy demands. Thus, polycations exert considerable detrimental effects on melanoma cells at concentrations better tolerated by epidermal melanocytes and act synergistically with vemurafenib in effectuating bioenergetic crisis, DNA damage and cell death selectively in melanoma cells. Mechanistic understanding of this synergy could lead to the development of macromolecular and polymer therapeutics with structural attributes that encompass even greater cancer-specific cytotoxicity, and provide strategies for tailor-made combination therapies.
    Keywords:  Bioenergetics; Melanoma; Mitochondria; Polycations; Polyethylenimine; Vemurafenib resistance
    DOI:  https://doi.org/10.1016/j.jconrel.2019.07.032
  19. Immunity. 2019 Jul 13. pii: S1074-7613(19)30287-0. [Epub ahead of print]
    Treg Cells Promote the SREBP1-Dependent Metabolic Fitness of Tumor-Promoting Macrophages via Repression of CD8+ T Cell-Derived Interferon-γ.
    Chang Liu, Maria Chikina, Rahul Deshpande, Ashley V Menk, Ting Wang, Tracy Tabib, Erin A Brunazzi, Kate M Vignali, Ming Sun, Donna B Stolz, Robert A Lafyatis, Wei Chen, Greg M Delgoffe, Creg J Workman, Stacy G Wendell, Dario A A Vignali.
      Regulatory T (Treg) cells are crucial for immune homeostasis, but they also contribute to tumor immune evasion by promoting a suppressive tumor microenvironment (TME). Mice with Treg cell-restricted Neuropilin-1 deficiency show tumor resistance while maintaining peripheral immune homeostasis, thereby providing a controlled system to interrogate the impact of intratumoral Treg cells on the TME. Using this and other genetic models, we showed that Treg cells shaped the transcriptional landscape across multiple tumor-infiltrating immune cell types. Treg cells suppressed CD8+ T cell secretion of interferon-γ (IFNγ), which would otherwise block the activation of sterol regulatory element-binding protein 1 (SREBP1)-mediated fatty acid synthesis in immunosuppressive (M2-like) tumor-associated macrophages (TAMs). Thus, Treg cells indirectly but selectively sustained M2-like TAM metabolic fitness, mitochondrial integrity, and survival. SREBP1 inhibition augmented the efficacy of immune checkpoint blockade, suggesting that targeting Treg cells or their modulation of lipid metabolism in M2-like TAMs could improve cancer immunotherapy.
    Keywords:  CD8(+) T cell-derived interferon-γ; Treg cells; tumor-promoting macrophages
    DOI:  https://doi.org/10.1016/j.immuni.2019.06.017
  20. Cancers (Basel). 2019 Jul 21. pii: E1027. [Epub ahead of print]11(7):
    Mutations in the ND2 Subunit of Mitochondrial Complex I Are Sufficient to Confer Increased Tumorigenic and Metastatic Potential to Cancer Cells.
    Joaquín Marco-Brualla, Sameer Al-Wasaby, Ruth Soler, Eduardo Romanos, Blanca Conde, Raquel Justo-Méndez, José A Enríquez, Patricio Fernández-Silva, Luis Martínez-Lostao, Martín Villalba, Raquel Moreno-Loshuertos, Alberto Anel.
      Multiprotein complexes of the mitochondrial electron transport chain form associations to generate supercomplexes. The relationship between tumor cell ability to assemble mitochondrial supercomplexes, tumorigenesis and metastasis has not been studied thoroughly. The mitochondrial and metabolic differences between L929dt cells, which lost matrix attachment and MHC-I expression, and their parental cell line L929, were analyzed. L929dt cells have lower capacity to generate energy through OXPHOS and lower respiratory capacity than parental L929 cells. Most importantly, L929dt cells show defects in mitochondrial supercomplex assembly, especially in those that contain complex I. These defects correlate with mtDNA mutations in L929dt cells at the ND2 subunit of complex I and are accompanied by a glycolytic shift. In addition, L929dt cells show higher in vivo tumorigenic and metastatic potential than the parental cell line. Cybrids with L929dt mitochondria in L929 nuclear background reproduce all L929dt properties, demonstrating that mitochondrial mutations are responsible for the aggressive tumor phenotype. In spite of their higher tumorigenic potential, L929dt or mitochondrial L929dt cybrid cells are sensitive both in vitro and in vivo to the PDK1 inhibitor dichloroacetate, which favors OXPHOS, suggesting benefits for the use of metabolic inhibitors in the treatment of especially aggressive tumors.
    Keywords:  ND2; complex I; cybrids; dichloroacetate; metastasis; mitochondria
    DOI:  https://doi.org/10.3390/cancers11071027
  21. Am J Physiol Renal Physiol. 2019 Jul 24.
    p53-cyclophilin D mediates renal tubular cell apoptosis in ischemia-reperfusion-induced acute kidney injury.
    Huan Yang, Ruizhao Li, Li Zhang, Shu Zhang, Wei Dong, Yuanhan Chen, Weidong Wang, Chunling Li, Zhiming Ye, Xingchen Zhao, Zhilian Li, Yanhua Wu, Mengxi Zhang, Shuangxin Liu, Zheng Dong, Xinling Liang.
      Ischemia-reperfusion-induced acute kidney injury (IR-AKI) favors mitochondrial permeability transition pore (mPTP) opening and subsequent cell death. Cyclophilin D (CypD) is an essential component of the mPTP, and recent findings implicate the p53-CypD complex in cell death. To evaluate the role of p53-CypD following IR-AKI, we tested the hypothesis that the p53-CypD complex mediates renal tubular cell apoptosis in IR-AKI via mPTP opening. The expression of p53 and cleaved caspase-3 was significantly increased in rats subjected to IR-AKI compared with the normal control and sham-operated control. The underlying mechanisms were determined using an in vitro model of ATP-depletion. The inhibition of mPTP opening using the CypD inhibitor cyclosporin A or a siRNA for p53 in ATP-depleted HK-2 cells prevented mitochondrial membrane depolarization and reduced apoptosis. Furthermore, p53 binds to CypD in ATP-depleted HK-2 cells. These results suggest that the p53-CypD complex mediates renal tubular cell apoptosis in IR-AKI via mPTP opening.
    Keywords:  cyclophilin D; ischemic renal injury; membrane permeability transition pore; p53
    DOI:  https://doi.org/10.1152/ajprenal.00072.2019
  22. Bioorg Med Chem Lett. 2019 Jul 06. pii: S0960-894X(19)30456-1. [Epub ahead of print]
    Inhibition of 3-phosphoglycerate dehydrogenase (PHGDH) by indole amides abrogates de novo serine synthesis in cancer cells.
    Edouard Mullarky, Jiayi Xu, Anita D Robin, David J Huggins, Andy Jennings, Naoyoshi Noguchi, Andrea Olland, Damodharan Lakshminarasimhan, Michael Miller, Daisuke Tomita, Mayako Michino, Taojunfeng Su, Guoan Zhang, Andrew W Stamford, Peter T Meinke, Stacia Kargman, Lewis C Cantley.
      Cancer cells reprogram their metabolism to support growth and to mitigate cellular stressors. The serine synthesis pathway has been identified as a metabolic pathway frequently altered in cancers and there has been considerable interest in developing pharmacological agents to target this pathway. Here, we report a series of indole amides that inhibit human 3-phosphoglycerate dehydrogenase (PHGDH), the enzyme that catalyzes the first committed step of the serine synthesis pathway. Using X-ray crystallography, we show that the indole amides bind the NAD+ pocket of PHGDH. Through structure-based optimization we were able to develop compounds with low nanomolar affinities for PHGDH in an enzymatic IC50 assay. In cellular assays, the most potent compounds inhibited de novo serine synthesis with low micromolar to sub-micromolar activities and these compounds successfully abrogated the proliferation of cancer cells in serine free media. The indole amide series reported here represent an important improvement over previously published PHGDH inhibitors as they are markedly more potent and their mechanism of action is better defined.
    Keywords:  3-Phosphoglycerate dehydrogenase; Cancer metabolism; Inhibitor; PHGDH; PHGDH inhibitor; Serine synthesis
    DOI:  https://doi.org/10.1016/j.bmcl.2019.07.011
  23. Methods Mol Biol. 2019 ;2030 57-68
    Quantification of Isotopologues of Amino Acids by Multiplexed Stable Isotope-Resolved Metabolomics Using Ultrahigh-Resolution Mass Spectrometry Coupled with Direct Infusion.
    Ye Yang, Teresa W-M Fan, Andrew N Lane, Richard M Higashi.
      Stable isotope-resolved metabolomics (SIRM) is increasingly used among researchers for metabolic studies including amino acid metabolism. However, the classical GC- or HPLC-based methods for amino acid quantification do not meet the needs for multiplexed stable isotope-enriched analysis by ultrahigh-resolution Fourier transform mass spectrometry (UHR-FTMS). This is due to insufficient acquisition time during chromatographic separations and large dynamic range in concentrations of analytes, which compromises detection and quantification of the numerous metabolite isotopologues present in crude extracts. This chapter discusses a modified ethyl chloroformate derivatization method to enable rapid quantitative analysis of stable isotope-enriched amino acids using direct infusion ion introduction coupled with UHR-FTMS.
    Keywords:  Amino acids; Chloroformate derivatization; Direct infusion nano-electrospray; Stable isotope-resolved metabolomics; Ultrahigh-resolution Fourier transform mass spectrometry
    DOI:  https://doi.org/10.1007/978-1-4939-9639-1_6
  24. Front Cell Neurosci. 2019 ;13 316
    Mitochondria Are Dynamically Transferring Between Human Neural Cells and Alexander Disease-Associated GFAP Mutations Impair the Astrocytic Transfer.
    Longfei Gao, Zhen Zhang, Jing Lu, Gang Pei.
      Mitochondria are the critical organelles for energy metabolism and cell survival in eukaryotic cells. Recent studies demonstrated that mitochondria can intercellularly transfer between mammalian cells. In neural cells, astrocytes transfer mitochondria into neurons in a CD38-dependent manner. Here, using co-culture system of neural cell lines, primary neural cells, and human pluripotent stem cell (hPSC)-derived neural cells, we further revealed that mitochondria dynamically transferred between astrocytes and also from neuronal cells into astrocytes, to which CD38/cyclic ADP-ribose signaling and mitochondrial Rho GTPases (MIRO1 and MIRO2) contributed. The transfer consequently elevated mitochondrial membrane potential in the recipient cells. By introducing Alexander disease (AxD)-associated hotspot mutations (R79C, R239C) into GFAP gene of hPSCs and subsequently inducing astrocyte differentiation, we found that GFAP mutations impaired mitochondrial transfer from astrocytes and reduced astrocytic CD38 expression. Thus, our study suggested that mitochondria dynamically transferred between neural cells and revealed that AxD-associated mutations in GFAP gene disrupted the astrocytic transfer, providing a potential pathogenic mechanism in AxD.
    Keywords:  Alexander disease; GFAP mutation; astrocytes; mitochondria; neuronal cells; transfer
    DOI:  https://doi.org/10.3389/fncel.2019.00316
  25. JCI Insight. 2019 Jul 23. pii: 126915. [Epub ahead of print]5
    Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer.
    Meifang Yu, Nicholas D Nguyen, Yanqing Huang, Daniel Lin, Tara N Fujimoto, Jessica M Molkentine, Amit Deorukhkar, Ya'an Kang, F Anthony San Lucas, Conrad J Fernandes, Eugene J Koay, Sonal Gupta, Haoqiang Ying, Albert C Koong, Joseph M Herman, Jason B Fleming, Anirban Maitra, Cullen M Taniguchi.
      Pancreatic ductal adenocarcinoma (PDAC) requires mitochondrial oxidative phosphorylation (OXPHOS) to fuel its growth, however, broadly inhibiting this pathway might also disrupt essential mitochondrial functions in normal tissues. PDAC cells exhibit abnormally fragmented mitochondria that are essential to its oncogenicity, but it was unclear if this mitochondrial feature was a valid therapeutic target. Here, we present evidence that normalizing the fragmented mitochondria of pancreatic cancer via the process of mitochondrial fusion reduces OXPHOS, which correlates with suppressed tumor growth and improved survival in preclinical models. Mitochondrial fusion was achieved by genetic or pharmacologic inhibition of dynamin related protein-1 (Drp1) or through overexpression of mitofusin-2 (Mfn2). Notably, we found that oral leflunomide, an FDA-approved arthritis drug, promoted a two-fold increase in Mfn2 expression in tumors and was repurposed as a chemotherapeutic agent, improving the median survival of mice with spontaneous tumors by 50% compared to vehicle. We found that the chief tumor suppressive mechanism of mitochondrial fusion was enhanced mitophagy, which proportionally reduced mitochondrial mass and ATP production. These data suggest that mitochondrial fusion is a specific and druggable regulator of pancreatic cancer growth that could be rapidly translated to the clinic.
    Keywords:  Cancer; Gastroenterology; Mitochondria; Mouse models; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.126915
  26. Protein Sci. 2019 Jul 25.
    An Overview of Structure, Function and Regulation of Pyruvate Kinases.
    Norbert Schormann, Katherine L Hayden, Paul Lee, Surajit Banerjee, Debasish Chattopadhyay.
      In the last step of glycolysis Pyruvate kinase catalyzes the irreversible conversion of ADP and phosphoenolpyruvate to ATP and pyruvic acid, both crucial for cellular metabolism. Thus pyruvate kinase plays a key role in controlling the metabolic flux and ATP production. The hallmark of the activity of different pyruvate kinases is their tight modulation by a variety of mechanisms including the use of a large number of physiological allosteric effectors in addition to their homotropic regulation by phosphoenolpyruvate. Binding of effectors signals precise and orchestrated movements in selected areas of the protein structure that alter the catalytic activity of these evolutionarily conserved enzymes with remarkably conserved architecture and sequences. While the diverse nature of the allosteric effectors has been discussed in the literature, the structural basis of their regulatory effects is still not well understood because of the lack of data representing conformations in various activation states. Results of recent studies on pyruvate kinases of different families suggest that members of evolutionarily related enzymes follow somewhat conserved allosteric strategies but evolutionarily distant members adopt different strategies. Here we review the structure and allosteric properties of pyruvate kinases of different families for which structural data are available. This article is protected by copyright. All rights reserved.
    Keywords:  Allosteric enzyme; Cryptosporidium; Crystal structure; Glycolysis; Holo-enzyme; Protein structure; Pyruvate Kinase
    DOI:  https://doi.org/10.1002/pro.3691
  27. Biofactors. 2019 Jul 25.
    Mitochondrial targets of metformin-Are they physiologically relevant?
    Alena Pecinová, Andrea Brázdová, Zdeněk Drahota, Josef Houštěk, Tomáš Mráček.
      Metformin is the most widely prescribed treatment of hyperglycemia and type II diabetes since 1970s. During the last 15 years, its popularity increased due to epidemiological evidence, that metformin administration reduces incidence of cancer. However, despite the ongoing effort of many researchers, the molecular mechanisms underlying antihyperglycemic or antineoplastic action of metformin remain elusive. Most frequently, metformin is associated with modulation of mitochondrial metabolism leading to lowering of blood glucose or activation of antitumorigenic pathways. Here we review the reported effects of metformin on mitochondrial metabolism and their potential relevance as effective molecular targets with beneficial therapeutic outcome.
    Keywords:  AMPK; metformin; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.1002/biof.1548
  28. Cell Metab. 2019 Jul 17. pii: S1550-4131(19)30319-5. [Epub ahead of print]
    The DNA Repair Nuclease MRE11A Functions as a Mitochondrial Protector and Prevents T Cell Pyroptosis and Tissue Inflammation.
    Yinyin Li, Yi Shen, Ke Jin, Zhenke Wen, Wenqiang Cao, Bowen Wu, Ru Wen, Lu Tian, Gerald J Berry, Jorg J Goronzy, Cornelia M Weyand.
      In the autoimmune disease rheumatoid arthritis (RA), CD4+ T cells promote pro-inflammatory effector functions by shunting glucose away from glycolysis and ATP production. Underlying mechanisms remain unknown, and here we implicate the DNA repair nuclease MRE11A in the cells' bioenergetic failure. MRE11A deficiency in RA T cells disrupted mitochondrial oxygen consumption and suppressed ATP generation. Also, MRE11A loss of function caused leakage of mitochondrial DNA (mtDNA) into the cytosol, triggering inflammasome assembly, caspase-1 activation, and pyroptotic cell death. Caspase-1 activation was frequent in lymph-node-residing T cells in RA patients. In vivo, pharmacologic and genetic inhibition of MRE11A resulted in tissue deposition of mtDNA, caspase-1 proteolysis, and aggressive tissue inflammation. Conversely, MRE11A overexpression restored mitochondrial fitness and shielded tissue from inflammatory attack. Thus, the nuclease MRE11A regulates a mitochondrial protection program, and MRE11A deficiency leads to DNA repair defects, energy production, and failure and loss of tissue homeostasis.
    Keywords:  ATP; DNA damage repair; MRE11A; T cell aging; caspase-1; inflammasome; mitochondrial DNA; pyroptosis; rheumatoid arthritis; tissue inflammation
    DOI:  https://doi.org/10.1016/j.cmet.2019.06.016
  29. Hepatology. 2019 Jul 25.
    Mitochondrial GCN5L1 regulates glutaminolysis, mTORC1 activity and murine liver regeneration.
    Lingdi Wang, Lu Zhu, Kaiyuan Wu, Yong Chen, Duck-Yeon Lee, Marjan Gucek, Michael N Sack.
      The regenerative capacity of the liver plays a protective role against hepatotoxins and impaired regeneration exacerbates liver dysfunction in non-alcoholic fatty liver disease (NAFLD). Mitochondrial bioenergetic and biosynthetic functions are important contributory factors in hepatic regeneration and the control of mitochondrial protein acetylation is implicated in the mitochondrial susceptibility to liver stressors. Here, we evaluated the role how GCN5L1, a mediator of mitochondrial metabolism and acetylation, in modulating murine liver regeneration in response to acute CCl4 -induced hepatotoxicity. Initial metabolomic screening found that liver GCN5L1 knockout (LKO) mice have augmented glutaminolysis. The absence of GCN5L1 modified the enzyme activity of the liver enriched glutaminase enzyme (GLS2) and GCN5L1 levels modulated GLS2 oligomerization and acetylation. This metabolic remodeling resulted in the elevation of α-ketoglutarate levels, which are known to activate mTORC1. This signaling pathway was induced with increased phosphorylation of S-6-kinase in LKO hepatocytes and inhibition of glutaminolysis reversed aberrant mTORC1 signaling. At the same time, glutaminolysis, the activity of GLS2 and activation of mTORC1 signaling were reversed by the genetic reintroduction of the mitochondrial isoform of GCN5L1 into LKO primary hepatocytes. Finally, LKO mice had a more robust regenerative capacity in response to CCl4 hepatoxicity and this response was blunted by both the mTORC1 inhibitor rapamycin and by pharmacologic blunting of glutaminolysis. CONCLUSION: These data point to a central role of glutaminolysis in modulating the regenerative capacity in liver. Furthermore, inhibition of mitochondrial GCN5L1 to augment liver regeneration may be a useful strategy in disease states linked to hepatotoxicity. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/hep.30876
  30. Int J Mol Sci. 2019 Jul 18. pii: E3520. [Epub ahead of print]20(14):
    Suppression of Brown Adipocyte Autophagy Improves Energy Metabolism by Regulating Mitochondrial Turnover.
    Donghwan Kim, Ji-Hye Kim, Young-Ho Kang, Je Seong Kim, Sung-Cheol Yun, Sang-Wook Kang, Youngsup Song.
      The high abundance of mitochondria and the expression of mitochondrial uncoupling protein 1 (UCP1) confer upon brown adipose tissue (BAT) the unique capacity to convert chemical energy into heat at the expense of ATP synthesis. It was long believed that BAT is present only in infants, and so, it was not considered as a potential therapeutic target for metabolic syndrome; however, the discovery of metabolically active BAT in adult humans has re-stimulated interest in the contributions of BAT metabolic regulation and dysfunction to health and disease. Here we demonstrate that brown adipocyte autophagy plays a critical role in the regulation BAT activity and systemic energy metabolism. Mice deficient in brown adipocyte autophagy due to BAT-specific deletion of Atg7-a gene essential for autophagosome generation-maintained higher mitochondrial content due to suppression of mitochondrial clearance and exhibited improved insulin sensitivity and energy metabolism. Autophagy was upregulated in BAT of older mice compared to younger mice, suggesting its involvement in the age-dependent decline of BAT activity and metabolic rate. These findings suggest that brown adipocyte autophagy plays a crucial role in metabolism and that targeting this pathway may be a potential therapeutic strategy for metabolic syndrome.
    Keywords:  aging; autophagy; brown adipose tissues; energy homeostasis; mitophagy
    DOI:  https://doi.org/10.3390/ijms20143520
  31. Nat Commun. 2019 Jul 19. 10(1): 3197
    Pptc7 is an essential phosphatase for promoting mammalian mitochondrial metabolism and biogenesis.
    Natalie M Niemi, Gary M Wilson, Katherine A Overmyer, F-Nora Vögtle, Lisa Myketin, Danielle C Lohman, Kathryn L Schueler, Alan D Attie, Chris Meisinger, Joshua J Coon, David J Pagliarini.
      Mitochondrial proteins are replete with phosphorylation, yet its functional relevance remains largely unclear. The presence of multiple resident mitochondrial phosphatases, however, suggests that protein dephosphorylation may be broadly important for calibrating mitochondrial activities. To explore this, we deleted the poorly characterized matrix phosphatase Pptc7 from mice using CRISPR-Cas9 technology. Strikingly, Pptc7-/- mice exhibit hypoketotic hypoglycemia, elevated acylcarnitines and serum lactate, and die soon after birth. Pptc7-/- tissues have markedly diminished mitochondrial size and protein content despite normal transcript levels, and aberrantly elevated phosphorylation on select mitochondrial proteins. Among these, we identify the protein translocase complex subunit Timm50 as a putative Pptc7 substrate whose phosphorylation reduces import activity. We further find that phosphorylation within or near the mitochondrial targeting sequences of multiple proteins could disrupt their import rates and matrix processing. Overall, our data define Pptc7 as a protein phosphatase essential for proper mitochondrial function and biogenesis during the extrauterine transition.
    DOI:  https://doi.org/10.1038/s41467-019-11047-6
  32. Nat Commun. 2019 Jul 19. 10(1): 3194
    A novel rapamycin analog is highly selective for mTORC1 in vivo.
    Katherine H Schreiber, Sebastian I Arriola Apelo, Deyang Yu, Jacqueline A Brinkman, Michael C Velarde, Faizan A Syed, Chen-Yu Liao, Emma L Baar, Kathryn A Carbajal, Dawn S Sherman, Denise Ortiz, Regina Brunauer, Shany E Yang, Stelios T Tzannis, Brian K Kennedy, Dudley W Lamming.
      Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In cells, DL001 efficiently represses elevated mTORC1 activity and restores normal gene expression to cells lacking a functional tuberous sclerosis complex. Our results demonstrate that highly selective pharmacological inhibition of mTORC1 can be achieved in vivo, and that selective inhibition of mTORC1 significantly reduces the side effects associated with conventional rapalogs.
    DOI:  https://doi.org/10.1038/s41467-019-11174-0
  33. Biochim Biophys Acta Proteins Proteom. 2019 Jul 23. pii: S1570-9639(19)30141-4. [Epub ahead of print]
    Biochemical characterization of human D-2-hydroxyglutarate dehydrogenase and two disease related variants reveals the molecular cause of D-2-hydroxyglutaric aciduria.
    Marina Toplak, Julia Brunner, Julia Schmidt, Peter Macheroux.
      D-2-hydroxyglutaric aciduria is a neurometabolic disorder, characterized by the accumulation of D-2-hydroxyglutarate (D-2HG) in human mitochondria. Increased levels of D-2HG are detected in humans exhibiting point mutations in the genes encoding isocitrate dehydrogenase, citrate carrier, the electron transferring flavoprotein (ETF) and its downstream electron acceptor ETF-ubiquinone oxidoreductase or D-2-hydroxyglutarate dehydrogenase (hD2HGDH). However, while the pathogenicity of several amino acid replacements in the former four proteins has been studied extensively, not much is known about the effect of certain point mutations on the biochemical properties of hD2HGDH. Therefore, we recombinantly produced wild type hD2HGDH as well as two recently identified disease-related variants (hD2HGDH-I147S and -V444A) and performed their detailed biochemical characterization. We could show that hD2HGDH is a FAD dependent protein, which is able to catalyze the oxidation of D-2HG and D-lactate to α-ketoglutarate and pyruvate, respectively. The two variants were obtained as apo-proteins and were thus catalytically inactive. The addition of FAD failed to restore enzymatic activity of the variants, indicating that the cofactor binding site is compromised by the single amino acid replacements. Further analyses revealed that both variants form aggregates that are apparently unable to bind the FAD cofactor. Since, D-2-hydroxyglutaric aciduria may also result from a loss of function of either the ETF or its downstream electron acceptor ETF-ubiquinone oxidoreductase, ETF may serve as the cognate electron acceptor of reduced hD2HGDH. Here, we show that hD2HGDH directly reduces recombinant human ETF, thus establishing a metabolic link between the oxidation of D-2-hydroxyglutarate and the mitochondrial electron transport chain.
    Keywords:  D-2-hydroxyglutarate; D-2-hydroxyglutaric aciduria; D-lactate; Electron transferring flavoprotein
    DOI:  https://doi.org/10.1016/j.bbapap.2019.07.008
  34. Proc Natl Acad Sci U S A. 2019 Jul 22. pii: 201818830. [Epub ahead of print]
    Increased ER-mitochondria tethering promotes axon regeneration.
    Soyeon Lee, Wei Wang, Jinyeon Hwang, Uk Namgung, Kyung-Tai Min.
      Translocation of the endoplasmic reticulum (ER) and mitochondria to the site of axon injury has been shown to facilitate axonal regeneration; however, the existence and physiological importance of ER-mitochondria tethering in the injured axons are unknown. Here, we show that a protein linking ER to mitochondria, the glucose regulated protein 75 (Grp75), is locally translated at axon injury site following axotomy, and that overexpression of Grp75 in primary neurons increases ER-mitochondria tethering to promote regrowth of injured axons. We find that increased ER-mitochondria tethering elevates mitochondrial Ca2+ and enhances ATP generation, thereby promoting regrowth of injured axons. Furthermore, intrathecal delivery of lentiviral vector encoding Grp75 to an animal with sciatic nerve crush injury enhances axonal regeneration and functional recovery. Together, our findings suggest that increased ER-mitochondria tethering at axonal injury sites may provide a therapeutic strategy for axon regeneration.
    Keywords:  ER; axon regeneration; mitochondria
    DOI:  https://doi.org/10.1073/pnas.1818830116
  35. J Clin Invest. 2019 Jul 22. pii: 125316. [Epub ahead of print]130
    ATP-binding cassette A1 deficiency causes cardiolipin-driven mitochondrial dysfunction in podocytes.
    G Michelle Ducasa, Alla Mitrofanova, Shamroop K Mallela, Xiaochen Liu, Judith Molina, Alexis Sloan, Christopher E Pedigo, Mengyuan Ge, Javier Varona Santos, Yanio Hernandez, Jin-Ju Kim, Cyrille Maugeais, Armando J Mendez, Viji Nair, Matthias Kretzler, George W Burke, Robert G Nelson, Yu Ishimoto, Reiko Inagi, Santanu Banerjee, Shaoyi Liu, Hazel H Szeto, Sandra Merscher, Flavia Fontanesi, Alessia Fornoni.
      Fibroblasts from patients with Tangier disease carrying ATP-binding cassette A1 (ABCA1) loss-of-function mutations are characterized by cardiolipin accumulation, a mitochondrial-specific phospholipid. Suppression of ABCA1 expression occurs in glomeruli from patients with diabetic kidney disease (DKD) and in human podocytes exposed to DKD sera collected prior to the development of DKD. We demonstrated that siRNA ABCA1 knockdown in podocytes led to reduced oxygen consumption capabilities associated with alterations in the oxidative phosphorylation (OXPHOS) complexes and with cardiolipin accumulation. Podocyte-specific deletion of Abca1 (Abca1fl/fl) rendered mice susceptible to DKD, and pharmacological induction of ABCA1 improved established DKD. This was not mediated by free cholesterol, as genetic deletion of sterol-o-acyltransferase-1 (SOAT1) in Abca1fl/fl mice was sufficient to cause free cholesterol accumulation but did not cause glomerular injury. Instead, cardiolipin mediates ABCA1-dependent susceptibility to podocyte injury, as inhibition of cardiolipin peroxidation with elamipretide improved DKD in vivo and prevented ABCA1-dependent podocyte injury in vitro and in vivo. Collectively, we describe a pathway definitively linking ABCA1 deficiency to cardiolipin-driven mitochondrial dysfunction. We demonstrated that this pathway is relevant to DKD and that ABCA1 inducers or inhibitors of cardiolipin peroxidation may each represent therapeutic strategies for the treatment of established DKD.
    Keywords:  Cholesterol; Chronic kidney disease; Metabolism; Mitochondria; Nephrology
    DOI:  https://doi.org/10.1172/JCI125316
  36. Nature. 2019 Jul 22.
    Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase.
    Ninghai Gan, Xiangkai Zhen, Yao Liu, Xiaolong Xu, Chunlin He, Jiazhang Qiu, Yancheng Liu, Grant M Fujimoto, Ernesto S Nakayasu, Biao Zhou, Lan Zhao, Kedar Puvar, Chittaranjan Das, Songying Ouyang, Zhao-Qing Luo.
      The bacterial pathogen Legionella pneumophila creates an intracellular niche permissive for its replication by extensively modulating host cell functions using hundreds of effector proteins delivered via its Dot/Icm secretion system1. Among these, members of the SidE family (SidEs) regulate multiple cellular processes by a unique phosphoribosyl ubiquitination mechanism that bypasses the canonical ubiquitination machinery2-4. The activity of SidEs is regulated by SidJ, another Dot/Icm effector5, but the mechanism of such regulation is not completely understood6,7. Here we demonstrate that SidJ inhibits the activity of SidEs by inducing covalent attachment of glutamate moieties to E860 of SdeA, which is one of the catalytic residues for the mono-ADP-ribosyltransferase activity involved in ubiquitin activation2. The inhibition by SidJ is spatially restricted in host cells because its activity requires the eukaryote-specific protein calmodulin (CaM). We solved a structure of SidJ-CaM in complex with adenosine monophosphate (AMP) and found that the ATP utilized is cleaved at the α phosphate position by SidJ which in the absence of glutamate or modifiable SdeA undergoes self-AMPylation. Our results reveal an unprecedented mechanism of regulation in bacterial pathogenicity in which a glutamylation reaction that inhibits the activity of virulence factors is activated by host factor-dependent acyl-adenylation.
    DOI:  https://doi.org/10.1038/s41586-019-1439-1
  37. J Biol Chem. 2019 Jul 26. pii: jbc.RA119.009203. [Epub ahead of print]
    Mitochondrial cysteinyl-tRNA synthetase is expressed via alternative transcriptional initiation regulated by energy metabolism in yeast cells.
    Akira Nishimura, Ryo Nasuno, Yuki Yoshikawa, Minkyung Jung, Tomoaki Ida, Tetsuro Matsunaga, Masanobu Morita, Hiroshi Takagi, Hozumi Motohashi, Takaaki Akaike.
      Eukaryotes typically utilize two distinct aminoacyl-tRNA synthetase isoforms, one for cytosolic and one for mitochondrial protein synthesis. However, the genome of budding yeast (Saccharomyces cerevisiae) contains only one cysteinyl-tRNA synthetase gene (YNL247W, also known as CRS1). In this study, we report that CRS1 encodes both cytosolic and mitochondrial isoforms. The 5'-cDNA end method and GFP reporter gene analyses indicated that yeast CRS1 expression yields two classes of mRNAs through alternative transcription starts: a long mRNA containing a mitochondrial targeting sequence and a short mRNA lacking this targeting sequence. We found that the mitochondrial Crs1 is the product of translation from the first initiation AUG codon on the long mRNA, whereas the cytosolic Crs1 is produced from the second in-frame AUG codon on the short mRNA. Genetic analysis and a ChIP assay revealed that the transcription factor heme activator protein (Hap) complex, which is involved in mitochondrial biogenesis, determines the transcription start sites of the CRS1 gene. We also noted that the Hap complex-dependent initiation is regulated according to the needs of mitochondrial energy production. The results of our study indicate energy-dependent initiation of alternative transcription of CRS1 that results in production of two Crs1 isoforms, a finding that suggests Crs1's potential involvement in mitochondrial energy metabolism in yeast.
    Keywords:  Hap complex; alternative transcription; aminoacyl tRNA synthetase; cysteinyl-tRNA synthetase; energy metabolism; gene regulation; mitochondrial bioenergetics; transcription; transcriptional start site; yeast
    DOI:  https://doi.org/10.1074/jbc.RA119.009203
  38. J Mol Biol. 2019 Jul 17. pii: S0022-2836(19)30450-4. [Epub ahead of print]
    Metabolomics Analysis of Nutrient Metabolism in β-Cells.
    Peter Spégel, Hindrik Mulder.
      The islets of Langerhans harbor multiple endocrine cell-types that continuously respond to circulating nutrient levels in order to adjust their secretion of catabolic and anabolic hormones. Stimulus-secretion coupling in these cells is largely of metabolic nature, i.e. metabolism of nutrient fuels yields signals that trigger and amplify secretion of hormones. Hence, metabolism in this micro-organ is in a major way in control of whole-body metabolism. Therefore, insights into islet metabolism is critical to understand how secretion of insulin is regulated and why it is perturbed in type 2 diabetes. Metabolomics aims at characterizing a wide spectrum of metabolites in cells, tissues and body fluids. For this reason, this technique is well-suited to supply information on stimulus-secretion coupling. Here, we summarize metabolomics studies in islets and β-cells, highlight important discoveries that would have been difficult to make without this technology but also raise awareness of challenges and bottlenecks that curtail its use in metabolic research.
    Keywords:  Diabetes; Mass spectrometry; Metabolite profiling; Pancreatic beta-cell; Stimulus-secretion coupling
    DOI:  https://doi.org/10.1016/j.jmb.2019.07.020
  39. Nat Med. 2019 Jul 22.
    Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome.
    Xinyu Qi, Chuyu Yun, Lulu Sun, Jialin Xia, Qing Wu, Ying Wang, Lina Wang, Yangming Zhang, Xianyi Liang, Liying Wang, Frank J Gonzalez, Andrew D Patterson, Huiying Liu, Liangshan Mu, Zehong Zhou, Yue Zhao, Rong Li, Ping Liu, Chao Zhong, Yanli Pang, Changtao Jiang, Jie Qiao.
      Polycystic ovary syndrome (PCOS) is characterized by androgen excess, ovulatory dysfunction and polycystic ovaries1, and is often accompanied by insulin resistance2. The mechanism of ovulatory dysfunction and insulin resistance in PCOS remains elusive, thus limiting the development of therapeutics. Improved metabolic health is associated with a relatively high microbiota gene content and increased microbial diversity3,4. This study aimed to investigate the impact of the gut microbiota and its metabolites on the regulation of PCOS-associated ovarian dysfunction and insulin resistance. Here, we report that Bacteroides vulgatus was markedly elevated in the gut microbiota of individuals with PCOS, accompanied by reduced glycodeoxycholic acid and tauroursodeoxycholic acid levels. Transplantation of fecal microbiota from women with PCOS or B. vulgatus-colonized recipient mice resulted in increased disruption of ovarian functions, insulin resistance, altered bile acid metabolism, reduced interleukin-22 secretion and infertility. Mechanistically, glycodeoxycholic acid induced intestinal group 3 innate lymphoid cell IL-22 secretion through GATA binding protein 3, and IL-22 in turn improved the PCOS phenotype. This finding is consistent with the reduced levels of IL-22 in individuals with PCOS. This study suggests that modifying the gut microbiota, altering bile acid metabolism and/or increasing IL-22 levels may be of value for the treatment of PCOS.
    DOI:  https://doi.org/10.1038/s41591-019-0509-0
  40. Proc Natl Acad Sci U S A. 2019 Jul 24. pii: 201902346. [Epub ahead of print]
    Identification of evolutionary and kinetic drivers of NAD-dependent signaling.
    Mathias Bockwoldt, Dorothée Houry, Marc Niere, Toni I Gossmann, Ines Reinartz, Alexander Schug, Mathias Ziegler, Ines Heiland.
      Nicotinamide adenine dinucleotide (NAD) provides an important link between metabolism and signal transduction and has emerged as central hub between bioenergetics and all major cellular events. NAD-dependent signaling (e.g., by sirtuins and poly-adenosine diphosphate [ADP] ribose polymerases [PARPs]) consumes considerable amounts of NAD. To maintain physiological functions, NAD consumption and biosynthesis need to be carefully balanced. Using extensive phylogenetic analyses, mathematical modeling of NAD metabolism, and experimental verification, we show that the diversification of NAD-dependent signaling in vertebrates depended on 3 critical evolutionary events: 1) the transition of NAD biosynthesis to exclusive usage of nicotinamide phosphoribosyltransferase (NamPT); 2) the occurrence of nicotinamide N-methyltransferase (NNMT), which diverts nicotinamide (Nam) from recycling into NAD, preventing Nam accumulation and inhibition of NAD-dependent signaling reactions; and 3) structural adaptation of NamPT, providing an unusually high affinity toward Nam, necessary to maintain NAD levels. Our results reveal an unexpected coevolution and kinetic interplay between NNMT and NamPT that enables extensive NAD signaling. This has implications for therapeutic strategies of NAD supplementation and the use of NNMT or NamPT inhibitors in disease treatment.
    Keywords:  NAD pathway dynamics and evolution; NAD-dependent signaling and biosynthesis; mathematical modeling; nicotinamide N-methyltransferase (NNMT); nicotinamide phosphoribosyltransferase (NamPT)
    DOI:  https://doi.org/10.1073/pnas.1902346116
  41. Sports (Basel). 2019 Jul 11. pii: E170. [Epub ahead of print]7(7):
    Exercise-Induced Mitohormesis for the Maintenance of Skeletal Muscle and Healthspan Extension.
    Robert V Musci, Karyn L Hamilton, Melissa A Linden.
      Oxidative damage is one mechanism linking aging with chronic diseases including the progressive loss of skeletal muscle mass and function called sarcopenia. Thus, mitigating oxidative damage is a potential avenue to prevent or delay the onset of chronic disease and/or extend healthspan. Mitochondrial hormesis (mitohormesis) occurs when acute exposure to stress stimulates adaptive mitochondrial responses that improve mitochondrial function and resistance to stress. For example, an acute oxidative stress via mitochondrial superoxide production stimulates the activation of endogenous antioxidant gene transcription regulated by the redox sensitive transcription factor Nrf2, resulting in an adaptive hormetic response. In addition, acute stresses such as aerobic exercise stimulate the expansion of skeletal muscle mitochondria (i.e., mitochondrial biogenesis), constituting a mitohormetic response that protects from sarcopenia through a variety of mechanisms. This review summarized the effects of age-related declines in mitochondrial and redox homeostasis on skeletal muscle protein homeostasis and highlights the mitohormetic mechanisms by which aerobic exercise mitigates these age-related declines and maintains function. We discussed the potential efficacy of targeting the Nrf2 signaling pathway, which partially mediates adaptation to aerobic exercise, to restore mitochondrial and skeletal muscle function. Finally, we highlight knowledge gaps related to improving redox signaling and make recommendations for future research.
    Keywords:  aging; exercise; healthspan; mitochondrial function; mitohormesis; redox homeostasis; sarcopenia; skeletal muscle
    DOI:  https://doi.org/10.3390/sports7070170
  42. JCI Insight. 2019 Jul 25. pii: 129398. [Epub ahead of print]4(14):
    Serine and 1-carbon metabolism are required for HIF-mediated protection against retinopathy of prematurity.
    Charandeep Singh, George Hoppe, Vincent Tran, Leah McCollum, Youstina Bolok, Weilin Song, Amit Sharma, Henri Brunengraber, Jonathan E Sears.
      We determined which metabolic pathways are activated by hypoxia-inducible factor 1-mediated (HIF-1-mediated) protection against oxygen-induced retinopathy (OIR) in newborn mice, the experimental correlate to retinopathy of prematurity, a leading cause of infant blindness. HIF-1 coordinates the change from oxidative to glycolytic metabolism and mediates flux through serine and 1-carbon metabolism (1CM) in hypoxic and cancer cells. We used untargeted metabolite profiling in vivo to demonstrate that hypoxia mimesis activates serine/1CM. Both [13C6] glucose labeling of metabolites in ex vivo retinal explants as well as in vivo [13C3] serine labeling of metabolites followed in liver lysates strongly suggest that retinal serine is primarily derived from hepatic glycolytic carbon and not from retinal glycolytic carbon in newborn pups. In HIF-1α2lox/2lox albumin-Cre-knockout mice, reduced or near-0 levels of serine/glycine further demonstrate the hepatic origin of retinal serine. Furthermore, inhibition of 1CM by methotrexate blocked HIF-mediated protection against OIR. This demonstrated that 1CM participates in protection induced by HIF-1 stabilization. The urea cycle also dominated pathway enrichment analyses of plasma samples. The dependence of retinal serine on hepatic HIF-1 and the upregulation of the urea cycle emphasize the importance of the liver to remote protection of the retina.
    Keywords:  Angiogenesis; Metabolism; Retinopathy
    DOI:  https://doi.org/10.1172/jci.insight.129398
  43. Autophagy. 2019 Jul 24. 1-7
    SQSTM1/p62 promotes mitochondrial ubiquitination independently of PINK1 and PRKN/parkin in mitophagy.
    Tatsuya Yamada, Ted M Dawson, Toru Yanagawa, Miho Iijima, Hiromi Sesaki.
      The ubiquitination of mitochondrial proteins labels damaged mitochondria for degradation through mitophagy. We recently developed an in vivo system in which mitophagy is slowed by inhibiting mitochondrial division through knockout of Dnm1l/Drp1, a dynamin related GTPase that mediates mitochondrial division. Using this system, we revealed that the ubiquitination of mitochondrial proteins required SQSTM1/p62, but not the ubiquitin E3 ligase PRKN/parkin, during mitophagy. Here, we tested the role of PINK1, a mitochondrial protein kinase that activates mitophagy by phosphorylating ubiquitin, in mitochondrial ubiquitination by knocking out Pink1 in dnm1l-knockout liver. We found mitochondrial ubiquitination did not decrease in the absence of PINK1; instead, PINK1 was required for the degradation of MFN1 (mitofusin 1) and MFN2, two homologous outer membrane proteins that mediate mitochondrial fusion in dnm1l-knockout hepatocytes. These data suggest that mitochondrial ubiquitination is promoted by SQSTM1 independently of PINK1 and PRKN during mitophagy. PINK1 and PRKN appear to control the balance between mitochondrial division and fusion in vivo. Abbreviations: DNM1L/DRP1: dynamin 1-like; KEAP1: kelch-like ECH-associated protein 1; KO: knockout; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MFN1/2: mitofusin 1/2; OPA1: OPA1, mitochondrial dynamin like GTPase; PDH: pyruvate dehydrogenase E1; PINK1: PTEN induced putative kinase 1; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase.
    Keywords:  Dnm1l/Drp1; PINK1; PRKN/parkin; mitochondria; mitochondrial division; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2019.1643185
  44. Am J Physiol Heart Circ Physiol. 2019 Jul 26.
    Both gain and loss of Nampt function promote pressure-overload-induced heart failure.
    Jaemin Byun, Shin-Ichi Oka, Nobushige Imai, Chun-Yang Huang, Guersom Ralda, Peiyong Zhai, Yoshiyuki Ikeda, Shohei Ikeda, Junichi Sadoshima.
      The heart requires high energy production, but metabolic ability declines in the failing heart. Nicotinamide phosphoribosyl-transferase (Nampt) is a rate-limiting enzyme in the salvage pathway of NAD synthesis. NAD is directly involved in various metabolic processes and may indirectly regulate metabolic gene expression through Sirt1, an NAD-dependent protein deacetylase. However, how Nampt regulates cardiac function and metabolism in the failing heart is poorly understood. Here we show that pressure-overload (PO)-induced heart failure is exacerbated in both systemic Nampt heterozygous knockout (Nampt+/-) mice and mice with cardiac-specific Nampt overexpression (Tg-Nampt). The NAD level declined in Nampt+/- mice under PO (Wild: 377, Nampt+/-: 119 (pmol/mg tissue), p=0.028). In cultured cardiomyocytes, Nampt knockdown diminished mitochondrial NAD content and ATP production (relative ATP production: Wild:1, Nampt knockdown: 0.56, p=0.0068), suggesting that downregulation of Nampt induces mitochondrial dysfunction. On the other hand, the NAD level was increased in Tg-Nampt mice at baseline but not during PO, possibly due to increased consumption of NAD by Sirt1. The expression of Sirt1 was increased in Tg-Nampt mice, in association with reduced overall protein acetylation. PO-induced downregulation of metabolic genes was exacerbated in Tg-Nampt mice. In cultured cardiomyocytes, Nampt and Sirt1 cooperatively suppressed mitochondrial proteins and ATP production, thereby promoting mitochondrial dysfunction. In addition, Nampt overexpression upregulated inflammatory cytokines, including TNFa and MCP-1. Thus, endogenous Nampt maintains cardiac function and metabolism in the failing heart, whereas Nampt overexpression is detrimental during PO, possibly due to excessive activation of Sirt1, suppression of mitochondrial function, and upregulation of proinflammatory mechanisms.
    Keywords:  Heart failure; Metabolism; NAD; Nampt; Sirtuins
    DOI:  https://doi.org/10.1152/ajpheart.00222.2019
  45. APMIS. 2019 Jul 25.
    L-serine: a neglected amino acid with a potential therapeutic role in diabetes.
    Laurits J Holm, Karsten Buschard.
      L-serine is classified as a nonessential amino acid, however, L-serine is indispensable having a central role in a broad range of cellular processes. Growing evidence suggests a role for L-serine in the development of diabetes mellitus and its related complications, with L-serine being positively correlated to insulin secretion and sensitivity. L-serine metabolism is altered in type 1, type 2, and gestational diabetes and L-serine supplementations improve glucose homeostasis, mitochondrial function, and reduces neuronal death. Additionally, L-serine lowers the incidence of autoimmune diabetes in NOD mice. Dietary supplementations of L-serine are generally regarded as safe (GRAS) by the FDA. Therefore, we believe that L-serine should be considered as an emerging therapeutic option in diabetes, although work remains in order to fully understand the role of L-serine in diabetes. This article is protected by copyright. All rights reserved.
    Keywords:  Deoxysphingolipids; Diabetes-related complications; L-serine; Type 1 diabetes; Type 2 diabetes
    DOI:  https://doi.org/10.1111/apm.12987
  46. J Biol Chem. 2019 Jul 23. pii: jbc.RA119.008743. [Epub ahead of print]
    De novo synthesis of serine and glycine fuels purine nucleotide biosynthesis in human lung cancer tissues.
    Teresa W M Fan, Ronald C Bruntz, Ye Yang, Huan Song, Yelena Chernyavskaya, Pan Deng, Yan Zhang, Parag P Shah, Levi J Beverly, Zhen Qi, Angela L Mahan, Richard M Higashi, Chi V Dang, Andrew N Lane.
      Nucleotide synthesis is essential to proliferating cells but the preferred precursors for de novo biosynthesis are not defined in human cancer tissues. We have employed multiplexed Stable Isotope Resolved Metabolomics (mSIRM) to track the metabolism of 13C6-glucose, D2-glycine, 13C2-glycine, and D3-serine into purine nucleotides in freshly resected cancerous and matched non-cancerous lung tissues from non-small cell lung cancer (NSCLC) patients and compared the metabolism with established NSCLC PC9 and A549 cell lines in vitro.  Surprisingly, 13C6-glucose was the best carbon source for purine synthesis in human NSCLC tissues, in contrast to the non-cancerous lung tissues from the same patient, which showed lower mitotic indices and MYC expression. We also observed that D3-Ser was preferentially incorporated into purine rings over D2-glycine in both tissues and cell lines. MYC suppression attenuated 13C6-glucose, D3-serine, and 13C2-glycine incorporation into purines and reduced proliferation in PC9 but not in A549 cells. Using detailed kinetic modeling, we showed that the preferred use of glucose as a carbon source for purine ring synthesis in NSCLC tissues involves cytoplasmic activation/compartmentation of the glucose-to-serine pathway and enhanced reversed one-carbon fluxes that attenuate exogenous serine incorporation into purines. Our findings also indicate that the substrate for de novo nucleotide synthesis differs profoundly between cancer cell lines and fresh human lung cancer tissues; the latter preferred glucose to exogenous serine or glycine but not the former. This distinction in substrate utilization in purine synthesis in human cancer tissues should be considered when targeting one-carbon metabolism for cancer therapy.
    Keywords:  dynamic compartmentation; ex vivo human lung tissue slice cultures; lung cancer; metabolic tracer; metabolism; multiplexed Stable Isotope-Resolved Metabolomics (mSIRM); nucleoside/nucleotide biosynthesis; one-carbon metabolism
    DOI:  https://doi.org/10.1074/jbc.RA119.008743
  47. Sci Rep. 2019 Jul 19. 9(1): 10521
    PI3K/mTOR inhibition of IDH1 mutant glioma leads to reduced 2HG production that is associated with increased survival.
    Georgios Batsios, Pavithra Viswanath, Elavarasan Subramani, Chloe Najac, Anne Marie Gillespie, Romelyn Delos Santos, Abigail R Molloy, Russell O Pieper, Sabrina M Ronen.
      70-90% of low-grade gliomas and secondary glioblastomas are characterized by mutations in isocitrate dehydrogenase 1 (IDHmut). IDHmut produces the oncometabolite 2-hydroxyglutarate (2HG), which drives tumorigenesis in these tumors. The phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway represents an attractive therapeutic target for IDHmut gliomas, but noninvasive indicators of drug target modulation are lacking. The goal of this study was therefore to identify magnetic resonance spectroscopy (MRS)-detectable metabolic biomarkers associated with IDHmut glioma response to the dual PI3K/(mTOR) inhibitor XL765. 1H-MRS of two cell lines genetically modified to express IDHmut showed that XL765 induced a significant reduction in several intracellular metabolites including 2HG. Importantly, examination of an orthotopic IDHmut tumor model showed that enhanced animal survival following XL765 treatment was associated with a significant in vivo 1H-MRS detectable reduction in 2HG but not with significant inhibition in tumor growth. Further validation is required, but our results indicate that 2HG could serve as a potential noninvasive MRS-detectable metabolic biomarker of IDHmut glioma response to PI3K/mTOR inhibition.
    DOI:  https://doi.org/10.1038/s41598-019-47021-x
  48. J Cell Sci. 2019 Jul 22. pii: jcs.231886. [Epub ahead of print]
    Depletion of phosphatidylinositol 4-phosphate at the Golgi translocates K-Ras to mitochondria.
    Taylor E Miller, Karen M Henkels, Mary Huddleston, Richard Salisbury, Saber M Hussain, Atsuo T Sasaki, Kwang-Jin Cho.
      Ras proteins are small GTPases localized to the plasma membrane (PM), which regulate cellular proliferation, apoptosis and differentiation. After a series of posttranslational modifications, H- and N-Ras traffic to the PM from the Golgi via the classical exocytic pathway, but the exact mechanism of K-Ras trafficking to the PM from the ER is not fully characterized. ATP5G1 is one of the three proteins that compose subunit c of the F0 complex of the mitochondrial ATP synthase. In this study, we show that overexpression of the mitochondrial targeting sequence of ATP5G1 perturbs glucose metabolism, inhibits oncogenic K-Ras signaling, and redistributes phosphatidylserine (PtdSer) to mitochondria and other endomembranes, resulting in K-Ras translocation to mitochondria. Also, it depletes phosphatidylinositol (PI) 4-phosphate (P) at the Golgi. Glucose supplementation restores PtdSer and K-Ras PM localization and PI4P at the Golgi. We further show that inhibition of the Golgi-localized PI4-kinases (PI4Ks) translocates K-Ras, and PtdSer to mitochondria and endomembranes, respectively. We conclude that PI4P at the Golgi regulates the PM localization of PtdSer and K-Ras.
    Keywords:  Golgi; K-Ras; Mitochondria; Phosphatidylinositol 4-kinase; Phosphatidylinositol 4-phosphate; Phosphatidylserine
    DOI:  https://doi.org/10.1242/jcs.231886
  49. Cancers (Basel). 2019 Jul 20. pii: E1026. [Epub ahead of print]11(7):
    Spatiotemporal pH Heterogeneity as a Promoter of Cancer Progression and Therapeutic Resistance.
    David E Korenchan, Robert R Flavell.
      Dysregulation of pH in solid tumors is a hallmark of cancer. In recent years, the role of altered pH heterogeneity in space, between benign and aggressive tissues, between individual cancer cells, and between subcellular compartments, has been steadily elucidated. Changes in temporal pH-related processes on both fast and slow time scales, including altered kinetics of bicarbonate-CO2 exchange and its effects on pH buffering and gradual, progressive changes driven by changes in metabolism, are further implicated in phenotypic changes observed in cancers. These discoveries have been driven by advances in imaging technologies. This review provides an overview of intra- and extracellular pH alterations in time and space reflected in cancer cells, as well as the available technology to study pH spatiotemporal heterogeneity.
    Keywords:  acidosis; carbonic anhydrase; hyperpolarized 13C MRI; interstitial pH; lactic acid; magnetic resonance imaging; positron emission tomography; tumor heterogeneity; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers11071026
  50. Oncogene. 2019 Jul 22.
    Iron regulatory protein 2 is a suppressor of mutant p53 in tumorigenesis.
    Yanhong Zhang, Xiuli Feng, Jin Zhang, Minyi Chen, Eric Huang, Xinbin Chen.
      p53 is known to play a role in iron homeostasis and is required for FDXR-mediated iron metabolism via iron regulatory protein 2 (IRP2). Interestingly, p53 is frequently mutated in tumors wherein iron is often accumulated, suggesting that mutant p53 may exert its gain of function by altering iron metabolism. In this study, we found that FDXR deficiency decreased mutant p53 expression along with altered iron metabolism in p53R270H/- MEFs and cancer cells carrying mutant p53. Consistently, we found that decreased expression of mutant p53 by FDXR deficiency inhibited mutant p53-R270H to induce carcinoma and high grade pleomorphic sarcoma in FDXR+/-; p53R270H/- mice as compared with p53R270H/- mice. Moreover, we found that like its effect on wild-type p53, loss of IRP2 increased mutant p53 expression. However, unlike its effect to suppress cell growth in cells carrying wild-type p53, loss of IRP2 promoted cell growth in cancer cells expressing mutant p53. Finally, we found that ectopic expression of IRP2 suppressed cell growth in a mutant p53-dependent manner. Together, our data indicate that mutant p53 gain-of-function can be suppressed by IRP2 and FDXR deficiency, both of which may be explored to target tumors carrying mutant p53.
    DOI:  https://doi.org/10.1038/s41388-019-0876-5
  51. Nat Commun. 2019 Jul 26. 10(1): 3345
    Regulation of antitumour CD8 T-cell immunity and checkpoint blockade immunotherapy by Neuropilin-1.
    Marine Leclerc, Elodie Voilin, Gwendoline Gros, Stéphanie Corgnac, Vincent de Montpréville, Pierre Validire, Georges Bismuth, Fathia Mami-Chouaib.
      Neuropilin-1 (Nrp-1) is a marker for murine CD4+FoxP3+ regulatory T (Treg) cells, a subset of human CD4+ Treg cells, and a population of CD8+ T cells infiltrating certain solid tumours. However, whether Nrp-1 regulates tumour-specific CD8 T-cell responses is still unclear. Here we show that Nrp-1 defines a subset of CD8+ T cells displaying PD-1hi status and infiltrating human lung cancer. Interaction of Nrp-1 with its ligand semaphorin-3A inhibits migration and tumour-specific lytic function of cytotoxic T lymphocytes. In vivo, Nrp-1+PD-1hi CD8+ tumour-infiltrating lymphocytes (TIL) in B16F10 melanoma are enriched for tumour-reactive T cells exhibiting an exhausted state, expressing Tim-3, LAG-3 and CTLA-4 inhibitory receptors. Anti-Nrp-1 neutralising antibodies enhance the migration and cytotoxicity of Nrp-1+PD-1hi CD8+ TIL ex vivo, while in vivo immunotherapeutic blockade of Nrp-1 synergises with anti-PD-1 to enhance CD8+ T-cell proliferation, cytotoxicity and tumour control. Thus, Nrp-1 could be a target for developing combined immunotherapies.
    DOI:  https://doi.org/10.1038/s41467-019-11280-z
  52. JCI Insight. 2019 Jul 25. pii: 123231. [Epub ahead of print]4(14):
    Lipidomics unveils lipid dyshomeostasis and low circulating plasmalogens as biomarkers in a monogenic mitochondrial disorder.
    LSFC Consortium
      Mitochondrial dysfunction characterizes many rare and common age-associated diseases. The biochemical consequences, underlying clinical manifestations, and potential therapeutic targets, remain to be better understood. We tested the hypothesis that lipid dyshomeostasis in mitochondrial disorders goes beyond mitochondrial fatty acid β-oxidation, particularly in liver. This was achieved using comprehensive untargeted and targeted lipidomics in a case-control cohort of patients with Leigh syndrome French-Canadian variant (LSFC), a mitochondrial disease caused by mutations in LRPPRC, and in mice harboring liver-specific inactivation of Lrpprc (H-Lrpprc-/-). We discovered a plasma lipid signature discriminating LSFC patients from controls encompassing lower levels of plasmalogens and conjugated bile acids, which suggest perturbations in peroxisomal lipid metabolism. This premise was reinforced in H-Lrpprc-/- mice, which compared with littermates recapitulated a similar, albeit stronger peroxisomal metabolic signature in plasma and liver including elevated levels of very-long-chain acylcarnitines. These mice also presented higher transcript levels for hepatic markers of peroxisome proliferation in addition to lipid remodeling reminiscent of nonalcoholic fatty liver diseases. Our study underscores the value of lipidomics to unveil unexpected mechanisms underlying lipid dyshomeostasis ensuing from mitochondrial dysfunction herein implying peroxisomes and liver, which likely contribute to the pathophysiology of LSFC, but also other rare and common mitochondrial diseases.
    Keywords:  Cell Biology; Fatty acid oxidation; Metabolism; Mitochondria; Monogenic diseases
    DOI:  https://doi.org/10.1172/jci.insight.123231
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