bims-camemi 2022-11-06 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2022–11–06
forty-four papers selected by
Christian Frezza, Universität zu Köln

Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.
Tumor glycolysis, an essential sweet tooth of tumor cells.
Mitochondrial DNA quality control in the female germline requires a unique programmed mitophagy.
Mitochondrial signal transduction.
Mitochondria from the Outside in: The Relationship Between Inter-Organelle Crosstalk and Mitochondrial Internal Organization.
Parkin regulates adiposity by coordinating mitophagy with mitochondrial biogenesis in white adipocytes.
Coupling-dependent metabolic ultradian rhythms in confluent cells.
Heterogeneity of the cancer cell line metabolic landscape.
Adipose tissue macrophages exert systemic metabolic control by manipulating local iron concentrations.
Transient Systemic Autophagy Ablation Irreversibly Inhibits Lung Tumor Cell Metabolism and Promotes T-Cell Mediated Tumor Killing.
Selective advantage of epigenetically disrupted cancer cells via phenotypic inertia.
A specialized metabolic pathway partitions citrate in hydroxyapatite to impact mineralization of bones and teeth.
Identification of evolutionarily conserved regulators of muscle mitochondrial network organization.
Mitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure.
Metabolism and Colorectal Cancer.
AKT supports the metabolic fitness of multiple myeloma cells by restricting FOXO activity.
Opa1-mediated mitochondrial dynamics is important for osteoclast differentiation.
TMBIM5 is the Ca2+ /H+ antiporter of mammalian mitochondria.
A functional analysis of 180 cancer cell lines reveals conserved intrinsic metabolic programs.
Defining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis.
Metabolic regulation by p53 prevents R-loop-associated genomic instability.
Ultrasensitive sensors reveal the spatiotemporal landscape of lactate metabolism in physiology and disease.
Targeting PDAC metabolism: Environment determines what has GOT2 give.
Compartmentalized activities of HMGCS1 control cervical cancer radiosensitivity.
Mitochondrial uncoupling induces epigenome remodeling and promotes differentiation in neuroblastoma.
Plasticity of cancer invasion and energy metabolism.
Non-canonical phosphoglycerate dehydrogenase activity promotes liver cancer growth via mitochondrial translation and respiratory metabolism.
Spatial dynamic metabolomics identifies metabolic cell fate trajectories in human kidney differentiation.
V-ATPase/TORC1-mediated ATFS-1 translation directs mitochondrial UPR activation in C. elegans.
A genetically encoded fluorescent biosensor for detecting itaconate with subcellular resolution in living macrophages.
Thioredoxins regulate the metabolic fluxes throughout the tricarboxylic acid cycle and associated pathways in a light-independent manner.
MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling.
WNK kinases sense molecular crowding and rescue cell volume via phase separation.
ER-mitochondrial contact protein Miga regulates autophagy through Atg14 and Uvrag.
De novo serine biosynthesis from glucose predicts sex-specific response to antifolates in non-small cell lung cancer cell lines.
Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling.
Oxidized thioredoxin-1 restrains the NLRP1 inflammasome.
Spermidine Supplementation Enhances Immune Checkpoint Blockade Response.
SCF-SKP2 E3 ubiquitin ligase links mTORC1-ER stress-ISR with YAP activation in murine renal cystogenesis.
Cystathionine γ lyase S-sulfhydrates Drp1 to ameliorate heart dysfunction.
Cancer cells move and spread faster in thicker extracellular fluids.
Disruption of mTORC1 rescues neuronal overgrowth and synapse function dysregulated by Pten loss.
Lactic acid and lactate: revisiting the physiological roles in the tumor microenvironment.
FOXA2 drives lineage plasticity and KIT pathway activation in neuroendocrine prostate cancer.

Mol Cell. 2022 Oct 31. pii: S1097-2765(22)00962-5. [Epub ahead of print]

Reversal of mitochondrial malate dehydrogenase 2 enables anaplerosis via redox rescue in respiration-deficient cells.

Patricia Altea-Manzano, Anke Vandekeere, Joy Edwards-Hicks, Mar Roldan, Emily Abraham, Xhordi Lleshi, Ania Naila Guerrieri, Domenica Berardi, Jimi Wills, Jair Marques Junior, Asimina Pantazi, Juan Carlos Acosta, Rosario M Sanchez-Martin, Sarah-Maria Fendt, Miguel Martin-Hernandez, Andrew J Finch.

  Inhibition of the electron transport chain (ETC) prevents the regeneration of mitochondrial NAD+, resulting in cessation of the oxidative tricarboxylic acid (TCA) cycle and a consequent dependence upon reductive carboxylation for aspartate synthesis. NAD+ regeneration alone in the cytosol can rescue the viability of ETC-deficient cells. Yet, how this occurs and whether transfer of oxidative equivalents to the mitochondrion is required remain unknown. Here, we show that inhibition of the ETC drives reversal of the mitochondrial aspartate transaminase (GOT2) as well as malate and succinate dehydrogenases (MDH2 and SDH) to transfer oxidative NAD+ equivalents into the mitochondrion. This supports the NAD+-dependent activity of the mitochondrial glutamate dehydrogenase (GDH) and thereby enables anaplerosis-the entry of glutamine-derived carbon into the TCA cycle and connected biosynthetic pathways. Thus, under impaired ETC function, the cytosolic redox state is communicated into the mitochondrion and acts as a rheostat to support GDH activity and cell viability.

Keywords:  anaplerosis; cancer; cancer metabolism; metabolism; mitochondrion; redox; redox transfer; respiration

DOI:  https://doi.org/10.1016/j.molcel.2022.10.005
Semin Cancer Biol. 2022 Oct 28. pii: S1044-579X(22)00204-8. [Epub ahead of print]86(Pt 3): 1216-1230

Tumor glycolysis, an essential sweet tooth of tumor cells.

Sumana Paul, Saikat Ghosh, Sushil Kumar.

  Cancer cells undergo metabolic alterations to meet the immense demand for energy, building blocks, and redox potential. Tumors show glucose-avid and lactate-secreting behavior even in the presence of oxygen, a process known as aerobic glycolysis. Glycolysis is the backbone of cancer cell metabolism, and cancer cells have evolved various mechanisms to enhance it. Glucose metabolism is intertwined with other metabolic pathways, making cancer metabolism diverse and heterogeneous, where glycolysis plays a central role. Oncogenic signaling accelerates the metabolic activities of glycolytic enzymes, mainly by enhancing their expression or by post-translational modifications. Aerobic glycolysis ferments glucose into lactate which supports tumor growth and metastasis by various mechanisms. Herein, we focused on tumor glycolysis, especially its interactions with the pentose phosphate pathway, glutamine metabolism, one-carbon metabolism, and mitochondrial oxidation. Further, we describe the role and regulation of key glycolytic enzymes in cancer. We summarize the role of lactate, an end product of glycolysis, in tumor growth, and the metabolic adaptations during metastasis. Lastly, we briefly discuss limitations and future directions to improve our understanding of glucose metabolism in cancer.

Keywords:  Cancer metabolism; Lactate; Metastasis; Tumor glycolysis; metabolic adaptations

DOI:  https://doi.org/10.1016/j.semcancer.2022.09.007
Cell Metab. 2022 Nov 01. pii: S1550-4131(22)00456-9. [Epub ahead of print]34(11): 1809-1823.e6

Mitochondrial DNA quality control in the female germline requires a unique programmed mitophagy.

Jonathan M Palozzi, Swathi P Jeedigunta, Anastasia V Minenkova, Vernon L Monteiro, Zoe S Thompson, Toby Lieber, Thomas R Hurd.

  Mitochondria have their own DNA (mtDNA), which is susceptible to the accumulation of disease-causing mutations. To prevent deleterious mutations from being inherited, the female germline has evolved a conserved quality control mechanism that remains poorly understood. Here, through a large-scale screen, we uncover a unique programmed germline mitophagy (PGM) that is essential for mtDNA quality control. We find that PGM is developmentally triggered as germ cells enter meiosis by inhibition of the target of rapamycin complex 1 (TORC1). We identify a role for the RNA-binding protein Ataxin-2 (Atx2) in coordinating the timing of PGM with meiosis. We show that PGM requires the mitophagy receptor BNIP3, mitochondrial fission and translation factors, and members of the Atg1 complex, but not the mitophagy factors PINK1 and Parkin. Additionally, we report several factors that are critical for germline mtDNA quality control and show that pharmacological manipulation of one of these factors promotes mtDNA quality control.

Keywords:  autophagy; germ line; germline; mitochondria; mitochondrial DNA; mitophagy; mtDNA; purifying selection; quality control

DOI:  https://doi.org/10.1016/j.cmet.2022.10.005
Cell Metab. 2022 Nov 01. pii: S1550-4131(22)00459-4. [Epub ahead of print]34(11): 1620-1653

Mitochondrial signal transduction.

Martin Picard, Orian S Shirihai.

  The analogy of mitochondria as powerhouses has expired. Mitochondria are living, dynamic, maternally inherited, energy-transforming, biosynthetic, and signaling organelles that actively transduce biological information. We argue that mitochondria are the processor of the cell, and together with the nucleus and other organelles they constitute the mitochondrial information processing system (MIPS). In a three-step process, mitochondria (1) sense and respond to both endogenous and environmental inputs through morphological and functional remodeling; (2) integrate information through dynamic, network-based physical interactions and diffusion mechanisms; and (3) produce output signals that tune the functions of other organelles and systemically regulate physiology. This input-to-output transformation allows mitochondria to transduce metabolic, biochemical, neuroendocrine, and other local or systemic signals that enhance organismal adaptation. An explicit focus on mitochondrial signal transduction emphasizes the role of communication in mitochondrial biology. This framework also opens new avenues to understand how mitochondria mediate inter-organ processes underlying human health.

Keywords:  amplification; communication; energy; evolution; health; membrane potential; metabokines; mito-nuclear signaling; mitochondrial networks; mitokines; mitotypes; receptors; signal transduction; steroid hormones; stress responses; tissue-specific

DOI:  https://doi.org/10.1016/j.cmet.2022.10.008
Contact (Thousand Oaks). 2022 Jan-Dec;5:5

Mitochondria from the Outside in: The Relationship Between Inter-Organelle Crosstalk and Mitochondrial Internal Organization.

Jonathan R Friedman.

  A fundamental role of membrane-bound organelles is the compartmentalization and organization of cellular processes. Mitochondria perform an immense number of metabolic chemical reactions and to efficiently regulate these, the organelle organizes its inner membrane into distinct morphological domains, including its characteristic cristae membranes. In recent years, a structural feature of increasing apparent importance is the inter-connection between the mitochondrial exterior and other organelles at membrane contact sites (MCSs). Mitochondria form MCSs with almost every other organelle in the cell, including the endoplasmic reticulum, lipid droplets, and lysosomes, to coordinate global cellular metabolism with mitochondrial metabolism. However, these MCSs not only facilitate the transport of metabolites between organelles, but also directly impinge on the physical shape and functional organization inside mitochondria. In this review, we highlight recent advances in our understanding of how physical connections between other organelles and mitochondria both directly and indirectly influence the internal architecture of mitochondria.

Keywords:  Ca2+; cristae; endoplasmic reticulum; inner mitochondrial membrane; interorganelle (inter-organelle); lipid droplet; lysosome; mitochondrion (mitochondria); phospholipid

DOI:  https://doi.org/10.1177/25152564221133267
Nat Commun. 2022 Nov 04. 13(1): 6661

Parkin regulates adiposity by coordinating mitophagy with mitochondrial biogenesis in white adipocytes.

Timothy M Moore, Lijing Cheng, Dane M Wolf, Jennifer Ngo, Mayuko Segawa, Xiaopeng Zhu, Alexander R Strumwasser, Yang Cao, Bethan L Clifford, Alice Ma, Philip Scumpia, Orian S Shirihai, Thomas Q de Aguiar Vallim, Markku Laakso, Aldons J Lusis, Andrea L Hevener, Zhenqi Zhou.

Parkin, an E3 ubiquitin ligase, plays an essential role in mitochondrial quality control. However, the mechanisms by which Parkin connects mitochondrial homeostasis with cellular metabolism in adipose tissue remain unclear. Here, we demonstrate that Park2 gene (encodes Parkin) deletion specifically from adipose tissue protects mice against high-fat diet and aging-induced obesity. Despite a mild reduction in mitophagy, mitochondrial DNA content and mitochondrial function are increased in Park2 deficient white adipocytes. Moreover, Park2 gene deletion elevates mitochondrial biogenesis by increasing Pgc1α protein stability through mitochondrial superoxide-activated NAD(P)H quinone dehydrogenase 1 (Nqo1). Both in vitro and in vivo studies show that Nqo1 overexpression elevates Pgc1α protein level and mitochondrial DNA content and enhances mitochondrial activity in mouse and human adipocytes. Taken together, our findings indicate that Parkin regulates mitochondrial homeostasis by balancing mitophagy and Pgc1α-mediated mitochondrial biogenesis in white adipocytes, suggesting a potential therapeutic target in adipocytes to combat obesity and obesity-associated disorders.

DOI: https://doi.org/10.1038/s41467-022-34468-2
Proc Natl Acad Sci U S A. 2022 Nov 08. 119(45): e2211142119

Coupling-dependent metabolic ultradian rhythms in confluent cells.

Shuzhang Yang, Shin Yamazaki, Kimberly H Cox, Yi-Lin Huang, Evan W Miller, Joseph S Takahashi.

  Ultradian rhythms in metabolism and physiology have been described previously in mammals. However, the underlying mechanisms for these rhythms are still elusive. Here, we report the discovery of temperature-sensitive ultradian rhythms in mammalian fibroblasts that are independent of both the cell cycle and the circadian clock. The period in each culture is stable over time but varies in different cultures (ranging from 3 to 24 h). We show that transient, single-cell metabolic pulses are synchronized into stable ultradian rhythms across contacting cells in culture by gap junction-mediated coupling. Coordinated rhythms are also apparent for other metabolic and physiological measures, including plasma membrane potential (Δψp), intracellular glutamine, α-ketoglutarate, intracellular adenosine triphosphate (ATP), cytosolic pH, and intracellular calcium. Moreover, these ultradian rhythms require extracellular glutamine, several different ion channels, and the suppression of mitochondrial ATP synthase by α-ketoglutarate, which provides a key feedback mechanism. We hypothesize that cellular coupling and metabolic feedback can be used by cells to balance energy demands for survival.

Keywords:  cellular metabolism; gap junctions; ion channels; membrane potential; ultradian rhythms

DOI:  https://doi.org/10.1073/pnas.2211142119
Mol Syst Biol. 2022 11;18(11): e11006

Heterogeneity of the cancer cell line metabolic landscape.

David Shorthouse, Jenna Bradley, Susan E Critchlow, Claus Bendtsen, Benjamin A Hall.

  The unravelling of the complexity of cellular metabolism is in its infancy. Cancer-associated genetic alterations may result in changes to cellular metabolism that aid in understanding phenotypic changes, reveal detectable metabolic signatures, or elucidate vulnerabilities to particular drugs. To understand cancer-associated metabolic transformation, we performed untargeted metabolite analysis of 173 different cancer cell lines from 11 different tissues under constant conditions for 1,099 different species using mass spectrometry (MS). We correlate known cancer-associated mutations and gene expression programs with metabolic signatures, generating novel associations of known metabolic pathways with known cancer drivers. We show that metabolic activity correlates with drug sensitivity and use metabolic activity to predict drug response and synergy. Finally, we study the metabolic heterogeneity of cancer mutations across tissues, and find that genes exhibit a range of context specific, and more general metabolic control.

Keywords:  cancer; heterogeneity; metabolomics; mutation

DOI:  https://doi.org/10.15252/msb.202211006
Nat Metab. 2022 Nov 03.

Adipose tissue macrophages exert systemic metabolic control by manipulating local iron concentrations.

Nolwenn Joffin, Christy M Gliniak, Jan-Bernd Funcke, Vivian A Paschoal, Clair Crewe, Shiuhwei Chen, Ruth Gordillo, Christine M Kusminski, Da Young Oh, Werner J Geldenhuys, Philipp E Scherer.

Iron is essential to many fundamental biological processes, but its cellular compartmentalization and concentration must be tightly controlled. Although iron overload can contribute to obesity-associated metabolic deterioration, the subcellular localization and accumulation of iron in adipose tissue macrophages is largely unknown. Here, we show that macrophage mitochondrial iron levels control systemic metabolism in male mice by altering adipocyte iron concentrations. Using various transgenic mouse models to manipulate the macrophage mitochondrial matrix iron content in an inducible fashion, we demonstrate that lowering macrophage mitochondrial matrix iron increases numbers of M2-like macrophages in adipose tissue, lowers iron levels in adipocytes, attenuates inflammation and protects from high-fat-diet-induced metabolic deterioration. Conversely, elevating macrophage mitochondrial matrix iron increases M1-like macrophages and iron levels in adipocytes, exacerbates inflammation and worsens high-fat-diet-induced metabolic dysfunction. These phenotypes are robustly reproduced by transplantation of a small amount of fat from transgenic to wild-type mice. Taken together, we identify macrophage mitochondrial iron levels as a crucial determinant of systemic metabolic homeostasis in mice.

DOI: https://doi.org/10.1038/s42255-022-00664-z
Autophagy. 2022 Oct 31.

Transient Systemic Autophagy Ablation Irreversibly Inhibits Lung Tumor Cell Metabolism and Promotes T-Cell Mediated Tumor Killing.

Kyle Nunn, Jessie Yanxiang Guo.

  Macroautophagy/autophagy is a highly conserved catabolic process pivotal to cellular homeostasis and support of tumorigenesis. Being a potential therapeutic target for cancer, we have worked to understand the implications of autophagy inhibition both systemically, and tumor-specifically. We utilized inducible expression of Atg5 shRNA to temporally control autophagy levels in a reversible manner to study the effects of tumor-intrinsic and systemic autophagic loss and restoration on established KrasG12D/+;trp53-/- (KP) lung tumor growth. We reported that transient systemic ATG5 loss significantly reduces KP lung tumor growth. Through in vivo isotope tracing and metabolic flux analyses, we noted that systemic ATG5 knockdown significantly reduces the uptake of glucose and lactate in lung tumors, leading to impaired TCA cycle metabolism and biosynthesis. Additionally, we observed an increased tumor T cell infiltration in the absence of systemic ATG5, which is essential for T cell-mediated tumor killing. Moreover, the impaired tumor metabolism and increased T cell infiltration are sustained when autophagy is restored in a short term. Finally, we found that intermittent systemic ATG5 knockdown, a mock therapy situation, significantly prolongs the lifespan of mice bearing KP lung tumors. Our findings lay the proof of concept for inhibition of autophagy as a valid approach to cancer therapy.

Keywords:  KRAS; autophagy; cancer metabolism; cancer therapy; immune evasion; lung tumor

DOI:  https://doi.org/10.1080/15548627.2022.2141534
Cancer Cell. 2022 Oct 27. pii: S1535-6108(22)00493-7. [Epub ahead of print]

Selective advantage of epigenetically disrupted cancer cells via phenotypic inertia.

Ioannis Loukas, Fabrizio Simeoni, Marta Milan, Paolo Inglese, Harshil Patel, Robert Goldstone, Philip East, Stephanie Strohbuecker, Richard Mitter, Bhavik Talsania, Wenhao Tang, Colin D H Ratcliffe, Erik Sahai, Vahid Shahrezaei, Paola Scaffidi.

  The evolution of established cancers is driven by selection of cells with enhanced fitness. Subclonal mutations in numerous epigenetic regulator genes are common across cancer types, yet their functional impact has been unclear. Here, we show that disruption of the epigenetic regulatory network increases the tolerance of cancer cells to unfavorable environments experienced within growing tumors by promoting the emergence of stress-resistant subpopulations. Disruption of epigenetic control does not promote selection of genetically defined subclones or favor a phenotypic switch in response to environmental changes. Instead, it prevents cells from mounting an efficient stress response via modulation of global transcriptional activity. This "transcriptional numbness" lowers the probability of cell death at early stages, increasing the chance of long-term adaptation at the population level. Our findings provide a mechanistic explanation for the widespread selection of subclonal epigenetic-related mutations in cancer and uncover phenotypic inertia as a cellular trait that drives subclone expansion.

Keywords:  adaptation; cancer epigenetics; chromatin modifiers; environmental stress; mechanisms of cancer evolution; mutations; pan-cancer; plasticity; subclonal; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2022.10.002
Proc Natl Acad Sci U S A. 2022 Nov 08. 119(45): e2212178119

A specialized metabolic pathway partitions citrate in hydroxyapatite to impact mineralization of bones and teeth.

Naomi Dirckx, Qian Zhang, Emily Y Chu, Robert J Tower, Zhu Li, Shenghao Guo, Shichen Yuan, Pratik A Khare, Cissy Zhang, Angela Verardo, Lucy O Alejandro, Angelina Park, Marie-Claude Faugere, Stephen L Helfand, Martha J Somerman, Ryan C Riddle, Rafael de Cabo, Anne Le, Klaus Schmidt-Rohr, Thomas L Clemens.

  Citrate is a critical metabolic substrate and key regulator of energy metabolism in mammalian cells. It has been known for decades that the skeleton contains most (>85%) of the body's citrate, but the question of why and how this metabolite should be partitioned in bone has received singularly little attention. Here, we show that osteoblasts use a specialized metabolic pathway to regulate uptake, endogenous production, and the deposition of citrate into bone. Osteoblasts express high levels of the membranous Na+-dependent citrate transporter solute carrier family 13 member 5 (Slc13a5) gene. Inhibition or genetic disruption of Slc13a5 reduced osteogenic citrate uptake and disrupted mineral nodule formation. Bones from mice lacking Slc13a5 globally, or selectively in osteoblasts, showed equivalent reductions in cortical thickness, with similarly compromised mechanical strength. Surprisingly, citrate content in mineral from Slc13a5-/- osteoblasts was increased fourfold relative to controls, suggesting the engagement of compensatory mechanisms to augment endogenous citrate production. Indeed, through the coordinated functioning of the apical membrane citrate transporter SLC13A5 and a mitochondrial zinc transporter protein (ZIP1; encoded by Slc39a1), a mediator of citrate efflux from the tricarboxylic acid cycle, SLC13A5 mediates citrate entry from blood and its activity exerts homeostatic control of cytoplasmic citrate. Intriguingly, Slc13a5-deficient mice also exhibited defective tooth enamel and dentin formation, a clinical feature, which we show is recapitulated in primary teeth from children with SLC13A5 mutations. Together, our results reveal the components of an osteoblast metabolic pathway, which affects bone strength by regulating citrate deposition into mineral hydroxyapatite.

Keywords:  Slc13a5; citrate; metabolism; mineralization; osteoblasts

DOI:  https://doi.org/10.1073/pnas.2212178119
Nat Commun. 2022 Nov 04. 13(1): 6622

Identification of evolutionarily conserved regulators of muscle mitochondrial network organization.

Prasanna Katti, Peter T Ajayi, Angel Aponte, Christopher K E Bleck, Brian Glancy.

Mitochondrial networks provide coordinated energy distribution throughout muscle cells. However, pathways specifying mitochondrial networks are incompletely understood and it is unclear how they might affect contractile fiber-type. Here, we show that natural energetic demands placed on Drosophila melanogaster muscles yield native cell-types among which contractile and mitochondrial network-types are regulated differentially. Proteomic analyses of indirect flight, jump, and leg muscles, together with muscles misexpressing known fiber-type specification factor salm, identified transcription factors H15 and cut as potential mitochondrial network regulators. We demonstrate H15 operates downstream of salm regulating flight muscle contractile and mitochondrial network-type. Conversely, H15 regulates mitochondrial network configuration but not contractile type in jump and leg muscles. Further, we find that cut regulates salm expression in flight muscles and mitochondrial network configuration in leg muscles. These data indicate cell type-specific regulation of muscle mitochondrial network organization through evolutionarily conserved transcription factors cut, salm, and H15.

DOI: https://doi.org/10.1038/s41467-022-34445-9
Nat Commun. 2022 Nov 04. 13(1): 6634

Mitochondrial Fission Process 1 controls inner membrane integrity and protects against heart failure.

Erminia Donnarumma, Michael Kohlhaas, Elodie Vimont, Etienne Kornobis, Thibault Chaze, Quentin Giai Gianetto, Mariette Matondo, Maryse Moya-Nilges, Christoph Maack, Timothy Wai.

Mitochondria are paramount to the metabolism and survival of cardiomyocytes. Here we show that Mitochondrial Fission Process 1 (MTFP1) is an inner mitochondrial membrane (IMM) protein that is dispensable for mitochondrial division yet essential for cardiac structure and function. Constitutive knockout of cardiomyocyte MTFP1 in mice resulted in a fatal, adult-onset dilated cardiomyopathy accompanied by extensive mitochondrial and cardiac remodeling during the transition to heart failure. Prior to the onset of disease, knockout cardiac mitochondria displayed specific IMM defects: futile proton leak dependent upon the adenine nucleotide translocase and an increased sensitivity to the opening of the mitochondrial permeability transition pore, with which MTFP1 physically and genetically interacts. Collectively, our data reveal new functions of MTFP1 in the control of bioenergetic efficiency and cell death sensitivity and define its importance in preventing pathogenic cardiac remodeling.

DOI: https://doi.org/10.1038/s41467-022-34316-3
Annu Rev Pathol. 2022 Nov 02.

Metabolism and Colorectal Cancer.

Joseph C Sedlak, Ömer H Yilmaz, Jatin Roper.

Reprogrammed metabolism is a hallmark of colorectal cancer (CRC). CRC cells are geared toward rapid proliferation, requiring nutrients and the removal of cellular waste in nutrient-poor environments. Intestinal stem cells (ISCs), the primary cell of origin for CRCs, must adapt their metabolism along the adenoma-carcinoma sequence to the unique features of their complex microenvironment that include interactions with intestinal epithelial cells, immune cells, stromal cells, commensal microbes, and dietary components. Emerging evidence implicates modifiable risk factors related to the environment, such as diet, as important in CRC pathogenesis. Here, we focus on describing the metabolism of ISCs, diets that influence CRC initiation, CRC genetics and metabolism, and the tumor microenvironment. The mechanistic links between environmental factors, metabolic adaptations, and the tumor microenvironment in enhancing or supporting CRC tumorigenesis are becoming better understood. Thus, greater knowledge of CRC metabolism holds promise for improved prevention and treatment. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 18 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-pathmechdis-031521-041113
Blood Adv. 2022 Nov 02. pii: bloodadvances.2022007383. [Epub ahead of print]

AKT supports the metabolic fitness of multiple myeloma cells by restricting FOXO activity.

Timon A Bloedjes, Guus de Wilde, Gerarda H Khan, Timothy Cody Ashby, John D Shaughnessy, Fenghuang Zhan, Riekelt H Houtkooper, Richard J Bende, Carel J M van Noesel, Marcel Spaargaren, Jeroen Ej Guikema.

Metabolic alterations are important cancer-associated features that allow cancer cell transformation and their survival under stress conditions. Multiple myeloma (MM) plasma cells show increased glycolysis and oxidative phosphorylation (OXPHOS), characteristics associated with recurrent genetic aberrations that drive the proliferation and survival of MM cells. The protein kinase B/AKT acts as a central node in cellular metabolism and is constitutively active in MM cells. Despite the known role of AKT in modulating cellular metabolism, little is known about the downstream factors of AKT that control the metabolic adaptability of MM cells. Here, we demonstrate that negative regulation of the forkhead box O (FOXO) transcription factors (TF) by AKT is crucial to prevent metabolic shutdown in MM cells, thus contributing to their metabolic adaptability. Our results demonstrate that the expression of several key metabolic genes involved in glycolysis, the tricarboxylic acid (TCA) cycle and OXPHOS, are repressed by FOXO TFs. Moreover, the FOXO-dependent repression of glycolysis- and TCA-associated genes correlates with a favorable prognosis in a large MM patient cohort. Our data suggest that repression of FOXO by AKT is essential to sustain glycolysis and the TCA cycle activity in MM cells, and as such predicts patient survival.

DOI: https://doi.org/10.1182/bloodadvances.2022007383
MicroPubl Biol. 2022 ;2022

Opa1-mediated mitochondrial dynamics is important for osteoclast differentiation.

Keizo Nishikawa, Hina Takegami, Hiromi Sesaki.

Opatic atrophy 1 (Opa1) is a mitochondrial GTPase that regulates mitochondrial fusion and maintenance of cristae architecture. Osteoclasts are mitochondrial rich-cells. However, the role of Opa1 in osteoclasts remains unclear. Here, we demonstrate that Opa1- deficient osteoclast precursor cells do not undergo efficient osteoclast differentiation and exhibit abnormal cristae morphology. Thus, Opa1 is a key factor in osteoclast differentiation through regulation of mitochondrial dynamics.

DOI: https://doi.org/10.17912/micropub.biology.000650
EMBO Rep. 2022 Nov 02. e54978

TMBIM5 is the Ca2+ /H+ antiporter of mammalian mitochondria.

Shane Austin, Ronald Mekis, Sami E M Mohammed, Mariafrancesca Scalise, Wen-An Wang, Michele Galluccio, Christina Pfeiffer, Tamara Borovec, Katja Parapatics, Dijana Vitko, Nora Dinhopl, Nicolas Demaurex, Keiryn L Bennett, Cesare Indiveri, Karin Nowikovsky.

  Mitochondrial Ca2+ ions are crucial regulators of bioenergetics and cell death pathways. Mitochondrial Ca2+ content and cytosolic Ca2+ homeostasis strictly depend on Ca2+ transporters. In recent decades, the major players responsible for mitochondrial Ca2+ uptake and release have been identified, except the mitochondrial Ca2+ /H+ exchanger (CHE). Originally identified as the mitochondrial K+ /H+ exchanger, LETM1 was also considered as a candidate for the mitochondrial CHE. Defining the mitochondrial interactome of LETM1, we identify TMBIM5/MICS1, the only mitochondrial member of the TMBIM family, and validate the physical interaction of TMBIM5 and LETM1. Cell-based and cell-free biochemical assays demonstrate the absence or greatly reduced Na+ -independent mitochondrial Ca2+ release in TMBIM5 knockout or pH-sensing site mutants, respectively, and pH-dependent Ca2+ transport by recombinant TMBIM5. Taken together, we demonstrate that TMBIM5, but not LETM1, is the long-sought mitochondrial CHE, involved in setting and regulating the mitochondrial proton gradient. This finding provides the final piece of the puzzle of mitochondrial Ca2+ transporters and opens the door to exploring its importance in health and disease, and to developing drugs modulating Ca2+ exchange.

Keywords:  LETM1; TMBIM5 (MICS1); mitochondrial Ca2+-H+ exchanger; mitochondrial metabolism; permeability transition pore

DOI:  https://doi.org/10.15252/embr.202254978
Mol Syst Biol. 2022 11;18(11): e11033

A functional analysis of 180 cancer cell lines reveals conserved intrinsic metabolic programs.

Sarah Cherkaoui, Stephan Durot, Jenna Bradley, Susan Critchlow, Sebastien Dubuis, Mauro Miguel Masiero, Rebekka Wegmann, Berend Snijder, Alaa Othman, Claus Bendtsen, Nicola Zamboni.

  Cancer cells reprogram their metabolism to support growth and invasion. While previous work has highlighted how single altered reactions and pathways can drive tumorigenesis, it remains unclear how individual changes propagate at the network level and eventually determine global metabolic activity. To characterize the metabolic lifestyle of cancer cells across pathways and genotypes, we profiled the intracellular metabolome of 180 pan-cancer cell lines grown in identical conditions. For each cell line, we estimated activity for 49 pathways spanning the entirety of the metabolic network. Upon clustering, we discovered a convergence into only two major metabolic types. These were functionally confirmed by 13 C-flux analysis, lipidomics, and analysis of sensitivity to perturbations. They revealed that the major differences in cancers are associated with lipid, TCA cycle, and carbohydrate metabolism. Thorough integration of these types with multiomics highlighted little association with genetic alterations but a strong association with markers of epithelial-mesenchymal transition. Our analysis indicates that in absence of variations imposed by the microenvironment, cancer cells adopt distinct metabolic programs which serve as vulnerabilities for therapy.

Keywords:  cancer metabolism; cell lines; metabolic flux; metabolomics; omics

DOI:  https://doi.org/10.15252/msb.202211033
Nat Commun. 2022 Oct 30. 13(1): 6497

Defining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis.

Yoshiharu Muto, Eryn E Dixon, Yasuhiro Yoshimura, Haojia Wu, Kohei Omachi, Nicolas Ledru, Parker C Wilson, Andrew J King, N Eric Olson, Marvin G Gunawan, Jay J Kuo, Jennifer H Cox, Jeffrey H Miner, Stephen L Seliger, Owen M Woodward, Paul A Welling, Terry J Watnick, Benjamin D Humphreys.

Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of end stage renal disease characterized by progressive expansion of kidney cysts. To better understand the cell types and states driving ADPKD progression, we analyze eight ADPKD and five healthy human kidney samples, generating single cell multiomic atlas consisting of ~100,000 single nucleus transcriptomes and ~50,000 single nucleus epigenomes. Activation of proinflammatory, profibrotic signaling pathways are driven by proximal tubular cells with a failed repair transcriptomic signature, proinflammatory fibroblasts and collecting duct cells. We identify GPRC5A as a marker for cyst-lining collecting duct cells that exhibits increased transcription factor binding motif availability for NF-κB, TEAD, CREB and retinoic acid receptors. We identify and validate a distal enhancer regulating GPRC5A expression containing these motifs. This single cell multiomic analysis of human ADPKD reveals previously unrecognized cellular heterogeneity and provides a foundation to develop better diagnostic and therapeutic approaches.

DOI: https://doi.org/10.1038/s41467-022-34255-z
Cell Rep. 2022 Nov 01. pii: S2211-1247(22)01429-2. [Epub ahead of print]41(5): 111568

Metabolic regulation by p53 prevents R-loop-associated genomic instability.

Emanuele Panatta, Alessio Butera, Eleonora Mammarella, Consuelo Pitolli, Alessandro Mauriello, Marcel Leist, Richard A Knight, Gerry Melino, Ivano Amelio.

  Gene-environment interactions can perturb the epigenome, triggering network alterations that participate in cancer pathogenesis. Integrating epigenomics, transcriptomics, and metabolic analyses with functional perturbation, we show that the tumor suppressor p53 preserves genomic integrity by empowering adequate levels of the universal methyl donor S-adenosylmethionine (SAM). In p53-deficient cells, perturbation of DNA methylation promotes derepression of heterochromatin, massive loss of histone H3-lysine 9 methylation, and consequent upregulation of satellite RNAs that triggers R-loop-associated replication stress and chromosomal aberrations. In p53-deficient cells, the inadequate SAM level underlies the inability to respond to perturbation because exogenous reintroduction of SAM represses satellite elements and restores the ability to cope with stress. Mechanistically, p53 transcriptionally controls genes involved in one-carbon metabolism, including Slc43a2, the methionine uptake transporter that is critical for SAM synthesis. Supported by clinical data, our findings shed light on the role of p53-mediated metabolism in preventing unscheduled R-loop-associated genomic instability.

Keywords:  CP: Molecular biology; cancer; chromosome stability; epigenetic integrity; p53; tumor suppression

DOI:  https://doi.org/10.1016/j.celrep.2022.111568
Cell Metab. 2022 Oct 22. pii: S1550-4131(22)00453-3. [Epub ahead of print]

Ultrasensitive sensors reveal the spatiotemporal landscape of lactate metabolism in physiology and disease.

Xie Li, Yinan Zhang, Lingyan Xu, Aoxue Wang, Yejun Zou, Ting Li, Li Huang, Weicai Chen, Shuning Liu, Kun Jiang, Xiuze Zhang, Dongmei Wang, Lijuan Zhang, Zhuo Zhang, Zeyi Zhang, Xianjun Chen, Wei Jia, Aihua Zhao, Xinfeng Yan, Haimeng Zhou, Linyong Zhu, Xinran Ma, Zhenyu Ju, Weiping Jia, Congrong Wang, Joseph Loscalzo, Yi Yang, Yuzheng Zhao.

  Despite its central importance in cellular metabolism, many details remain to be determined regarding subcellular lactate metabolism and its regulation in physiology and disease, as there is sensitive spatiotemporal resolution of lactate distribution, and dynamics remains a technical challenge. Here, we develop and characterize an ultrasensitive, highly responsive, ratiometric lactate sensor, named FiLa, enabling the monitoring of subtle lactate fluctuations in living cells and animals. Utilizing FiLa, we demonstrate that lactate is highly enriched in mammalian mitochondria and compile an atlas of subcellular lactate metabolism that reveals lactate as a key hub sensing various metabolic activities. In addition, FiLa sensors also enable direct imaging of elevated lactate levels in diabetic mice and facilitate the establishment of a simple, rapid, and sensitive lactate assay for point-of-care clinical screening. Thus, FiLa sensors provide powerful, broadly applicable tools for defining the spatiotemporal landscape of lactate metabolism in health and disease.

Keywords:  highly responsive lactate sensors; lactate metabolism; point-of-care clinical screening; real-time monitoring; subcellular lactate landscape

DOI:  https://doi.org/10.1016/j.cmet.2022.10.002
Cell Metab. 2022 Nov 01. pii: S1550-4131(22)00451-X. [Epub ahead of print]34(11): 1617-1619

Targeting PDAC metabolism: Environment determines what has GOT2 give.

Oliver J Newsom, Lucas B Sullivan.

Metabolic disruption is a mainstay of cancer therapy, prompting research aimed at identifying novel metabolic targets. Despite strong effects observed in culture, three recent studies found pancreatic tumors are refractory to disruption of the metabolic enzyme GOT2, revealing complex interactions within the tumor microenvironment that bypass its conventional metabolic roles.

DOI: https://doi.org/10.1016/j.cmet.2022.09.027
Cell Signal. 2022 Oct 31. pii: S0898-6568(22)00269-8. [Epub ahead of print] 110507

Compartmentalized activities of HMGCS1 control cervical cancer radiosensitivity.

Xiaomin Zhang, Congcong Sun, Jinliang Wan, Xiaoxue Zhang, Yanhan Jia, Chao Zhou.

  The underlying mechanisms by which cellular metabolism affects cervical cancer cell radiosensitivity remain poorly understood. Here, we found that loss of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1), a key enzyme catalyzing the conversion of acetoacetyl-CoA to HMG-CoA in the cholesterol biosynthesis pathway, sensitizes the cervical cancer cells to radiation. We observed a compartmentalized cellular distribution of HMGCS1 in nuclei, cytosol, and mitochondria of cervical cancer cells and found that cytosolic HMGCS1 and mitochondrial HMGCS1 contribute together to the regulation of radiosensitivity. Mechanistically, we show that cytosolic HMGCS1 regulates radiosensitivity via manipulating the cholesterol metabolism, while mitochondrial HMGCS1 controls mitochondrial gene expression, thereby sustaining the mitochondrial function of cervical cancer cells. Together, our study identifies HMGCS1 as a novel regulator of radiosensitivty in cervical cancer cells, providing a molecular link between altered cholesterol metabolism, mitochondrial respiration, and radiosensitivity. Thus, targeting HMGCS1 may improve the therapeutic outcome of cervical cancer radiotherapy.

Keywords:  Cervical cancer; Mitochondrial DNA expression; Mitochondrial function; Radiosensitivity

DOI:  https://doi.org/10.1016/j.cellsig.2022.110507
Cancer Res. 2022 Nov 01. pii: CAN-22-1029. [Epub ahead of print]

Mitochondrial uncoupling induces epigenome remodeling and promotes differentiation in neuroblastoma.

Haowen Jiang, Rachel L Greathouse, Sarah Jane Tiche, Man Zhao, Bo He, Yang Li, Albert M Li, Balint Forgo, Michaela Yip, Allison Li, Moriah Shih, Selene Banuelos, Meng-Ning Zhou, Joshua J Gruber, Erinn B Rankin, Zhen Hu, Hiroyuki Shimada, Bill Chiu, Jiangbin Ye.

The Warburg effect is the major metabolic hallmark of cancer. According to Warburg himself, the consequence of the Warburg effect is cell dedifferentiation. Therefore, reversing the Warburg effect might be an approach to restore cell differentiation in cancer. In this study, we used a mitochondrial uncoupler, niclosamide ethanolamine (NEN), to activate mitochondrial respiration, which induced neural differentiation in neuroblastoma cells. NEN treatment increased the nicotinamide adenine dinucleotide (NAD)+/NADH and pyruvate/lactate ratios and also the α-ketoglutarate (α-KG)/2- hydroxyglutarate (2-HG) ratio. Consequently, NEN treatment induced promoter CpG island demethylation and epigenetic landscape remodeling, activating the neural differentiation program. In addition, NEN treatment upregulated p53 but downregulated N-Myc and β-catenin signaling in neuroblastoma cells. Importantly, even under hypoxia, NEN treatment remained effective in inhibiting 2-HG generation, promoting DNA demethylation, and suppressing hypoxia-inducible factor signaling. Dietary NEN intervention reduced tumor growth rate, 2-HG levels, and expression of N-Myc and β-catenin in tumors in an orthotopic neuroblastoma mouse model. Integrative analysis indicated that NEN treatment upregulated favorable prognosis genes and downregulated unfavorable prognosis genes, which were defined using multiple neuroblastoma patient datasets. Altogether, these results suggest that mitochondrial uncoupling is an effective metabolic and epigenetic therapy for reversing the Warburg effect and inducing differentiation in neuroblastoma.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-1029
Trends Cell Biol. 2022 Oct 31. pii: S0962-8924(22)00231-8. [Epub ahead of print]

Plasticity of cancer invasion and energy metabolism.

Maria Parlani, Carolina Jorgez, Peter Friedl.

  Energy deprivation is a frequent adverse event in tumors that is caused by mutations, malperfusion, hypoxia, and nutrition deficit. The resulting bioenergetic stress leads to signaling and metabolic adaptation responses in tumor cells, secures survival, and adjusts migration activity. The kinetic responses of cancer cells to energy deficit were recently identified, including a switch of invasive cancer cells to energy-conservative amoeboid migration and an enhanced capability for distant metastasis. We review the energy programs employed by different cancer invasion modes including collective, mesenchymal, and amoeboid migration, as well as their interconversion in response to energy deprivation, and we discuss the consequences for metastatic escape. Understanding the energy requirements of amoeboid and other dissemination strategies offers rationales for improving therapeutic targeting of metastatic cancer progression.

Keywords:  amoeboid migration; cellular bioenergetics; metabolic stress; migration plasticity

DOI:  https://doi.org/10.1016/j.tcb.2022.09.009
EMBO J. 2022 Oct 31. e111550

Non-canonical phosphoglycerate dehydrogenase activity promotes liver cancer growth via mitochondrial translation and respiratory metabolism.

Ying Shu, Yijie Hao, Junru Feng, Haiying Liu, Shi-Ting Li, Jiaqian Feng, Zetan Jiang, Ling Ye, Yingli Zhou, Yuchen Sun, Zilong Zhou, Haoran Wei, Ping Gao, Huafeng Zhang, Linchong Sun.

  Phosphoglycerate dehydrogenase (PHGDH) is a key serine biosynthesis enzyme whose aberrant expression promotes various types of tumors. Recently, PHGDH has been found to have some non-canonical functions beyond serine biosynthesis, but its specific mechanisms in tumorigenesis remain unclear. Here, we show that PHGDH localizes to the inner mitochondrial membrane and promotes the translation of mitochondrial DNA (mtDNA)-encoded proteins in liver cancer cells. Mechanistically, we demonstrate that mitochondrial PHGDH directly interacts with adenine nucleotide translocase 2 (ANT2) and then recruits mitochondrial elongation factor G2 (mtEFG2) to promote mitochondrial ribosome recycling efficiency, thereby promoting mtDNA-encoded protein expression and subsequent mitochondrial respiration. Moreover, we show that treatment with a mitochondrial translation inhibitor or depletion of mtEFG2 diminishes PHGDH-mediated tumor growth. Collectively, our findings uncover a previously unappreciated function of PHGDH in tumorigenesis acting via promotion of mitochondrial translation and bioenergetics.

Keywords:  ANT2; PHGDH; liver cancer; mitochondrial translation; mtEFG2

DOI:  https://doi.org/10.15252/embj.2022111550
Cell Stem Cell. 2022 Nov 03. pii: S1934-5909(22)00426-X. [Epub ahead of print]29(11): 1580-1593.e7

Spatial dynamic metabolomics identifies metabolic cell fate trajectories in human kidney differentiation.

Gangqi Wang, Bram Heijs, Sarantos Kostidis, Rosalie G J Rietjens, Marije Koning, Lushun Yuan, Gesa L Tiemeier, Ahmed Mahfouz, Sébastien J Dumas, Martin Giera, Jesper Kers, Susana M Chuva de Sousa Lopes, Cathelijne W van den Berg, Bernard M van den Berg, Ton J Rabelink.

  Accumulating evidence demonstrates important roles for metabolism in cell fate determination. However, it is a challenge to assess metabolism at a spatial resolution that acknowledges both heterogeneity and cellular dynamics in its tissue microenvironment. Using a multi-omics platform to study cell-type-specific dynamics in metabolism in complex tissues, we describe the metabolic trajectories during nephrogenesis in the developing human kidney. Exploiting in situ analysis of isotopic labeling, a shift from glycolysis toward fatty acid β-oxidation was observed during the differentiation from the renal vesicle toward the S-shaped body and the proximal tubules. In addition, we show that hiPSC-derived kidney organoids are characterized by a metabolic immature phenotype that fails to use mitochondrial long-chain fatty acids for energy metabolism. Furthermore, supplementation of butyrate enhances tubular epithelial differentiation and maturation in cultured kidney organoids. Our findings highlight the relevance of understanding metabolic trajectories to efficiently guide stem cell differentiation.

Keywords:  MALDI-MSI; cell metabolism; fetal kidney development; hiPSC-derived kidney organoids; multi-omics metabolomics; nephrogenesis; proximal tubule development; single cell; spatial dynamic metabolomics

DOI:  https://doi.org/10.1016/j.stem.2022.10.008
J Cell Biol. 2023 Jan 02. pii: e202205045. [Epub ahead of print]222(1):

V-ATPase/TORC1-mediated ATFS-1 translation directs mitochondrial UPR activation in C. elegans.

Terytty Yang Li, Arwen W Gao, Xiaoxu Li, Hao Li, Yasmine J Liu, Amelia Lalou, Nagammal Neelagandan, Felix Naef, Kristina Schoonjans, Johan Auwerx.

To adapt mitochondrial function to the ever-changing intra- and extracellular environment, multiple mitochondrial stress response (MSR) pathways, including the mitochondrial unfolded protein response (UPRmt), have evolved. However, how the mitochondrial stress signal is sensed and relayed to UPRmt transcription factors, such as ATFS-1 in Caenorhabditis elegans, remains largely unknown. Here, we show that a panel of vacuolar H+-ATPase (v-ATPase) subunits and the target of rapamycin complex 1 (TORC1) activity are essential for the cytosolic relay of mitochondrial stress to ATFS-1 and for the induction of the UPRmt. Mechanistically, mitochondrial stress stimulates v-ATPase/Rheb-dependent TORC1 activation, subsequently promoting ATFS-1 translation. Increased translation of ATFS-1 upon mitochondrial stress furthermore relies on a set of ribosomal components but is independent of GCN-2/PEK-1 signaling. Finally, the v-ATPase and ribosomal subunits are required for mitochondrial surveillance and mitochondrial stress-induced longevity. These results reveal a v-ATPase-TORC1-ATFS-1 signaling pathway that links mitochondrial stress to the UPRmt through intimate crosstalks between multiple organelles.

DOI: https://doi.org/10.1083/jcb.202205045
Nat Commun. 2022 Nov 04. 13(1): 6562

A genetically encoded fluorescent biosensor for detecting itaconate with subcellular resolution in living macrophages.

Pengkai Sun, Zhenxing Zhang, Bin Wang, Caiyun Liu, Chao Chen, Ping Liu, Xinjian Li.

Itaconate is a newly discovered endogenous metabolite promoting an anti-inflammatory program during innate immune response, but the precise mechanisms underlying its effect remains poorly understood owing primarily to the limitations of available itaconate-monitoring techniques. Here, we develop and validate a genetically encoded fluorescent itaconate biosensor, BioITA, for directly monitoring itaconate dynamics in subcellular compartments of living macrophages. Utilizing BioITA, we monitor the itaconate dynamics in response to lipopolysaccharide (LPS) stimulation in the context of modulating itaconate transportation and metabolism. Moreover, we show that STING activation induces itaconate production, and injection of AAVs expressing cytosolic BioITA into mice allows directly reporting elevation of itaconate level in activated macrophages derived from LPS-injected mice. Thus, BioITA enables subcellular resolution imaging of itaconate in living macrophages.

DOI: https://doi.org/10.1038/s41467-022-34306-5
Plant Physiol Biochem. 2022 Oct 26. pii: S0981-9428(22)00476-4. [Epub ahead of print]193 36-49

Thioredoxins regulate the metabolic fluxes throughout the tricarboxylic acid cycle and associated pathways in a light-independent manner.

Nicole P Porto, Raissa S C Bret, Paulo V L Souza, Silvio A Cândido-Sobrinho, David B Medeiros, Alisdair R Fernie, Danilo M Daloso.

  The metabolic fluxes throughout the tricarboxylic acid cycle (TCAC) are inhibited in the light by the mitochondrial thioredoxin (TRX) system. However, it is unclear how this system orchestrates the fluxes throughout the TCAC and associated pathways in the dark. Here we carried out a13C-HCO3 labelling experiment in Arabidopsis leaves from wild type (WT) and mutants lacking TRX o1 (trxo1), TRX h2 (trxh2), or both NADPH-dependent TRX reductase A and B (ntra ntrb) exposed to 0, 30 and 60 min of dark or light conditions. No 13C-enrichment in TCAC metabolites in illuminated WT leaves was observed. However, increased succinate content was found in parallel to reductions in Ala in the light, suggesting the latter operates as an alternative carbon source for succinate synthesis. By contrast to WT, all mutants showed substantial changes in the content and 13C-enrichment in TCAC metabolites under both dark and light conditions. Increased 13C-enrichment in glutamine in illuminated trxo1 leaves was also observed, strengthening the idea that TRX o1 restricts in vivo carbon fluxes from glycolysis and the TCAC to glutamine. We further demonstrated that both photosynthetic and gluconeogenic fluxes toward glucose are increased in trxo1 and that the phosphoenolpyruvate carboxylase (PEPc)-mediated 13C-incorporation into malate is higher in trxh2 mutants, as compared to WT. Our results collectively provide evidence that TRX h2 and the mitochondrial NTR/TRX system regulate the metabolic fluxes throughout the TCAC and associated pathways, including glycolysis, gluconeogenesis and the synthesis of glutamine in a light-independent manner.

Keywords:  (13)C-positional labelling analysis; Metabolic fluxes; Metabolic regulation; NTRA; NTRB; TRX h2; TRX o1

DOI:  https://doi.org/10.1016/j.plaphy.2022.10.022
Nat Commun. 2022 Nov 02. 13(1): 6579

MYC promotes immune-suppression in triple-negative breast cancer via inhibition of interferon signaling.

Dario Zimmerli, Chiara S Brambillasca, Francien Talens, Jinhyuk Bhin, Renske Linstra, Lou Romanens, Arkajyoti Bhattacharya, Stacey E P Joosten, Ana Moises Da Silva, Nuno Padrao, Max D Wellenstein, Kelly Kersten, Mart de Boo, Maurits Roorda, Linda Henneman, Roebi de Bruijn, Stefano Annunziato, Eline van der Burg, Anne Paulien Drenth, Catrin Lutz, Theresa Endres, Marieke van de Ven, Martin Eilers, Lodewyk Wessels, Karin E de Visser, Wilbert Zwart, Rudolf S N Fehrmann, Marcel A T M van Vugt, Jos Jonkers.

The limited efficacy of immune checkpoint inhibitor treatment in triple-negative breast cancer (TNBC) patients is attributed to sparse or unresponsive tumor-infiltrating lymphocytes, but the mechanisms that lead to a therapy resistant tumor immune microenvironment are incompletely known. Here we show a strong correlation between MYC expression and loss of immune signatures in human TNBC. In mouse models of TNBC proficient or deficient of breast cancer type 1 susceptibility gene (BRCA1), MYC overexpression dramatically decreases lymphocyte infiltration in tumors, along with immune signature remodelling. MYC-mediated suppression of inflammatory signalling induced by BRCA1/2 inactivation is confirmed in human TNBC cell lines. Moreover, MYC overexpression prevents the recruitment and activation of lymphocytes in both human and mouse TNBC co-culture models. Chromatin-immunoprecipitation-sequencing reveals that MYC, together with its co-repressor MIZ1, directly binds promoters of multiple interferon-signalling genes, resulting in their downregulation. MYC overexpression thus counters tumor growth inhibition by a Stimulator of Interferon Genes (STING) agonist via suppressing induction of interferon signalling. Together, our data reveal that MYC suppresses innate immunity and facilitates tumor immune escape, explaining the poor immunogenicity of MYC-overexpressing TNBCs.

DOI: https://doi.org/10.1038/s41467-022-34000-6
Cell. 2022 Oct 25. pii: S0092-8674(22)01261-2. [Epub ahead of print]

WNK kinases sense molecular crowding and rescue cell volume via phase separation.

Cary R Boyd-Shiwarski, Daniel J Shiwarski, Shawn E Griffiths, Rebecca T Beacham, Logan Norrell, Daryl E Morrison, Jun Wang, Jacob Mann, William Tennant, Eric N Anderson, Jonathan Franks, Michael Calderon, Kelly A Connolly, Muhammad Umar Cheema, Claire J Weaver, Lubika J Nkashama, Claire C Weckerly, Katherine E Querry, Udai Bhan Pandey, Christopher J Donnelly, Dandan Sun, Aylin R Rodan, Arohan R Subramanya.

  When challenged by hypertonicity, dehydrated cells must recover their volume to survive. This process requires the phosphorylation-dependent regulation of SLC12 cation chloride transporters by WNK kinases, but how these kinases are activated by cell shrinkage remains unknown. Within seconds of cell exposure to hypertonicity, WNK1 concentrates into membraneless condensates, initiating a phosphorylation-dependent signal that drives net ion influx via the SLC12 cotransporters to restore cell volume. WNK1 condensate formation is driven by its intrinsically disordered C terminus, whose evolutionarily conserved signatures are necessary for efficient phase separation and volume recovery. This disorder-encoded phase behavior occurs within physiological constraints and is activated in vivo by molecular crowding rather than changes in cell size. This allows kinase activity despite an inhibitory ionic milieu and permits cell volume recovery through condensate-mediated signal amplification. Thus, WNK kinases are physiological crowding sensors that phase separate to coordinate a cell volume rescue response.

Keywords:  K-Cl cotransport; Na-K-2Cl cotransport; SLC12 cotransporter; WNK kinase; biomolecular condensates; cell volume regulation; hyperosmotic stress; macromolecular crowding; phase separation

DOI:  https://doi.org/10.1016/j.cell.2022.09.042
Cell Rep. 2022 Nov 01. pii: S2211-1247(22)01448-6. [Epub ahead of print]41(5): 111583

ER-mitochondrial contact protein Miga regulates autophagy through Atg14 and Uvrag.

Lingna Xu, Yunyi Qiu, Xufeng Wang, Weina Shang, Jian Bai, Kexin Shi, Hao Liu, Jun-Ping Liu, Liquan Wang, Chao Tong.

  Mitochondrial malfunction and autophagy defects are often concurrent phenomena associated with neurodegeneration. We show that Miga, a mitochondrial outer-membrane protein that regulates endoplasmic reticulum-mitochondrial contact sites (ERMCSs), is required for autophagy. Loss of Miga results in an accumulation of autophagy markers and substrates, whereas PI3P and Syx17 levels are reduced. Further experiments indicated that the fusion between autophagosomes and lysosomes is defective in Miga mutants. Miga binds to Atg14 and Uvrag; concordantly, Miga overexpression results in Atg14 and Uvrag recruitment to mitochondria. The heightened PI3K activity induced by Miga requires Uvrag, whereas Miga-mediated stabilization of Syx17 is dependent on Atg14. Miga-regulated ERMCSs are critical for PI3P formation but are not essential for the stabilization of Syx17. In summary, we identify a mitochondrial protein that regulates autophagy by recruiting two alternative components of the PI3K complex present at the ERMCSs.

Keywords:  CP: Cell biology; Drosophila; ER–mitochondrial contact; autophagy; lysosome; mitochondria

DOI:  https://doi.org/10.1016/j.celrep.2022.111583
iScience. 2022 Nov 18. 25(11): 105339

De novo serine biosynthesis from glucose predicts sex-specific response to antifolates in non-small cell lung cancer cell lines.

Jasmin Sponagel, Siddhartha Devarakonda, Joshua B Rubin, Jingqin Luo, Joseph E Ippolito.

  Lung cancer is the leading cause of cancer-related death. Intriguingly, males with non-small cell lung cancer (NSCLC) have a higher mortality rate than females. Here, we investigated the role of serine metabolism as a predictive marker for sensitivity to the antifolate pemetrexed in male and female NSCLC cell lines. Using [13C6] glucose tracing in NSCLC cell lines, we found that a subset of male cells generated significantly more serine from glucose than female cells. Higher serine biosynthesis was further correlated with increased sensitivity to pemetrexed in male cells only. Concordant sex differences in metabolic gene expression were evident in NSCLC and pan-cancer transcriptome datasets, suggesting a potential mechanism with wide-reaching applicability. These data were further validated by integrating antifolate drug cytotoxicity and metabolic pathway transcriptome data from pan-cancer cell lines. Together, these findings highlight the importance of considering sex differences in cancer metabolism to improve treatment for all patients.

Keywords:  Cancer; Cell biology; Cellular physiology

DOI:  https://doi.org/10.1016/j.isci.2022.105339
Cell Rep. 2022 Nov 01. pii: S2211-1247(22)01446-2. [Epub ahead of print]41(5): 111581

Arid1a loss potentiates pancreatic β-cell regeneration through activation of EGF signaling.

Cemre Celen, Jen-Chieh Chuang, Shunli Shen, Lin Li, Gianna Maggiore, Yuemeng Jia, Xin Luo, Austin Moore, Yunguan Wang, Jordan E Otto, Clayton K Collings, Zixi Wang, Xuxu Sun, Ibrahim Nassour, Jiyoung Park, Alexandra Ghaben, Tao Wang, Sam C Wang, Philipp E Scherer, Cigall Kadoch, Hao Zhu.

  The dynamic regulation of β-cell abundance is poorly understood. Since chromatin remodeling plays critical roles in liver regeneration, these mechanisms could be generally important for regeneration in other tissues. Here, we show that the ARID1A mammalian SWI/SNF complex subunit is a critical regulator of β-cell regeneration. Arid1a is highly expressed in quiescent β-cells but is physiologically suppressed when β-cells proliferate during pregnancy or after pancreas resection. Whole-body Arid1a knockout mice are protected against streptozotocin-induced diabetes. Cell-type and temporally specific genetic dissection show that β-cell-specific Arid1a deletion can potentiate β-cell regeneration in multiple contexts. Transcriptomic and epigenomic profiling of mutant islets reveal increased neuregulin-ERBB-NR4A signaling. Chemical inhibition of ERBB or NR4A1 blocks increased regeneration associated with Arid1a loss. Mammalian SWI/SNF (mSWI/SNF) complex activity is a barrier to β-cell regeneration in physiologic and disease states.

Keywords:  Arid1a; CP: Cell biology; CP: Developmental biology; EGFR/ERBB; NR4A nuclear receptors; NRG/EGF signaling; SWI/SNF; chromatin remodeling; diabetes; islets; β-cell regeneration

DOI:  https://doi.org/10.1016/j.celrep.2022.111581
Sci Immunol. 2022 Nov 11. 7(77): eabm7200

Oxidized thioredoxin-1 restrains the NLRP1 inflammasome.

Daniel P Ball, Lydia P Tsamouri, Alvin E Wang, Hsin-Che Huang, Charles D Warren, Qinghui Wang, Isabelle H Edmondson, Andrew R Griswold, Sahana D Rao, Darren C Johnson, Daniel A Bachovchin.

The danger signals that activate the NLRP1 inflammasome have not been established. Here, we report that the oxidized, but not the reduced, form of thioredoxin-1 (TRX1) binds to NLRP1. We found that oxidized TRX1 associates with the NACHT-LRR region of NLRP1 in an ATP-dependent process, forming a stable complex that restrains inflammasome activation. Consistent with these findings, patient-derived and ATPase-inactivating mutations in the NACHT-LRR region that cause hyperactive inflammasome formation interfere with TRX1 binding. Overall, this work strongly suggests that reductive stress, the cellular perturbation that will eliminate oxidized TRX1 and abrogate the TRX1-NLRP1 interaction, is a danger signal that activates the NLRP1 inflammasome.

DOI: https://doi.org/10.1126/sciimmunol.abm7200
Cancer Discov. 2022 Nov 04. OF1

Spermidine Supplementation Enhances Immune Checkpoint Blockade Response.

Spermidine enhances T-cell mitochondrial metabolism and the antitumor response to anti-PD-L1.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-196
J Clin Invest. 2022 Nov 03. pii: e153943. [Epub ahead of print]

SCF-SKP2 E3 ubiquitin ligase links mTORC1-ER stress-ISR with YAP activation in murine renal cystogenesis.

Dibyendu K Panda, Xiuying Bai, Yan Zhang, Nicholas A Stylianesis, Antonis E Koromilas, Mark L Lipman, Andrew C Karaplis.

  The Hippo pathway nuclear effector Yes-associated protein 1 (YAP) potentiates the progression of polycystic kidney disease (PKD) arising from ciliopathies. The mechanisms underlying the increase in YAP expression and transcriptional activity in PKD remain obscure. We observed that in kidneys from mice with juvenile cystic kidney (jck) ciliopathy, the aberrant hyperactivity of mechanistic target of rapamycin complex 1 (mTORC1) driven by ERK1/2 and PI3K/AKT cascades induced endoplasmic reticulum (ER) proteotoxic stress. To reduce it by reprogramming translation, the protein kinase R-like ER kinase (PERK)-eukaryotic initiation factor 2α (eIF2α) arm of the integrated stress response (ISR) was activated. PERK-mediated phosphorylation of eIF2α drove the selective translation of activating transcription factor 4 (ATF4), potentiating YAP expression. In parallel, YAP underwent K63-linked polyubiquitination by SCF-S-phase kinase-associated protein 2 (SKP2) E3 ubiquitin ligase, a Hippo-independent, nonproteolytic ubiquitination that enhances YAP nuclear trafficking and transcriptional activity in cancer cells. Defective ISR cellular adaptation to ER stress in eIF2α-phosphorylation-deficient jck mice further augmented YAP-mediated transcriptional activity and renal cyst growth. Conversely, pharmacological tuning down of ER stress-ISR activity and SKP2 expression in jck mice by administration of tauroursodeoxycholic acid (TUDCA) or tolvaptan, impeded these processes. Restoring ER homeostasis, and/or interfering with the SKP2-YAP interaction represent novel potential therapeutic avenues for stemming the progression of renal cystogenesis.

Keywords:  Chronic kidney disease; Nephrology

DOI:  https://doi.org/10.1172/JCI153943
Redox Biol. 2022 Oct 28. pii: S2213-2317(22)00291-9. [Epub ahead of print]58 102519

Cystathionine γ lyase S-sulfhydrates Drp1 to ameliorate heart dysfunction.

Dan Wu, Bo Tan, Yuanyuan Sun, Qingxun Hu.

  Hydrogen sulfide (H2S), produced by cystathionine γ lyase (CSE), is an important endogenous gasotransmitter to maintain heart function. However, the molecular mechanism for how H2S influences the mitochondrial morphology during heart failure remains poorly understood. Here, we found that CSE/H2S pathway mediated cardiac function and mitochondrial morphology through regulating dynamin related protein 1 (Drp1) activity and translocation. Mechanistically, elevation of H2S levels by CSE overexpression declined protein level, phosphorylation (Ser 616), oligomerization and GTPase activity of Drp1 by S-sulfhydration in mouse hearts. Interestingly, Drp1 S-sulfhydration directly competed with S-nitrosylation by nitric oxide at the specific cysteine 607. The non-S-sulfhydration of Drp1 mutation (C607A) attenuated the regulatory effect of H2S on Drp1 activation, mitochondrial fission and heart function. Moreover, the non-canonical role of Drp1 mediated isoprenaline-induced mitochondrial dysfunction and cardiomyocyte death through interaction with voltage-dependent anion channel 1. These results uncover that a novel mechanism that H2S S-sulfhydrated Drp1 at cysteine 607 to prevent heart failure through modulating its activity and mitochondrial translocation. Our findings also provide initial evidence demonstrating that Drp1 may be a critical regulator as well as an effective strategy for heart dysfunction.

Keywords:  Dynamin related protein 1; Heart failure; Hydrogen sulfide; Mitochondrial fission; S-Sulfhydration

DOI:  https://doi.org/10.1016/j.redox.2022.102519
Nature. 2022 Nov 02.

Cancer cells move and spread faster in thicker extracellular fluids.



Keywords:  Cancer; Cell biology

DOI:  https://doi.org/10.1038/d41586-022-03328-w
Cell Rep. 2022 Nov 01. pii: S2211-1247(22)01435-8. [Epub ahead of print]41(5): 111574

Disruption of mTORC1 rescues neuronal overgrowth and synapse function dysregulated by Pten loss.

Kamran Tariq, Erin Cullen, Stephanie A Getz, Andie K S Conching, Andrew R Goyette, Mackenzi L Prina, Wei Wang, Meijie Li, Matthew C Weston, Bryan W Luikart.

  Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a negative regulator of AKT/mTOR signaling pathway. Mutations in PTEN are found in patients with autism, epilepsy, or macrocephaly. In mouse models, Pten loss results in neuronal hypertrophy, hyperexcitability, seizures, and ASD-like behaviors. The underlying molecular mechanisms of these phenotypes are not well delineated. We determined which of the Pten loss-driven aberrations in neuronal form and function are orchestrated by downstream mTOR complex 1 (mTORC1). Rapamycin-mediated inhibition of mTORC1 prevented increase in soma size, migration, spine density, and dendritic overgrowth in Pten knockout dentate gyrus granule neurons. Genetic knockout of Raptor to disrupt mTORC1 complex formation blocked Pten loss-mediated neuronal hypertrophy. Electrophysiological recordings revealed that genetic disruption of mTORC1 rescued Pten loss-mediated increase in excitatory synaptic transmission. We have identified an essential role for mTORC1 in orchestrating Pten loss-driven neuronal hypertrophy and synapse formation.

Keywords:  CP: Cell biology; CP: Neuroscience; PTEN; Raptor; autism; dendrite; mTOR; rapamycin; synapse

DOI:  https://doi.org/10.1016/j.celrep.2022.111574
Trends Immunol. 2022 Oct 29. pii: S1471-4906(22)00213-7. [Epub ahead of print]

Lactic acid and lactate: revisiting the physiological roles in the tumor microenvironment.

Petya Apostolova, Erika L Pearce.

Lactic acid production has been regarded as a mechanism by which malignant cells escape immunosurveillance. Recent technological advances in mass spectrometry and the use of cell culture media with a physiological nutrient composition have shed new light on the role of lactic acid and its conjugate lactate in the tumor microenvironment. Here, we review novel work identifying lactate as a physiological carbon source for mammalian tumors and immune cells. We highlight evidence that its use as a substrate is distinct from the immunosuppressive acidification of the extracellular milieu by lactic acid protons. Together, data suggest that neutralizing the effects of intratumoral acidity while maintaining physiological lactate metabolism in cytotoxic CD8+ T cells should be pursued to boost anti-tumor immunity.

DOI: https://doi.org/10.1016/j.it.2022.10.005
Cancer Cell. 2022 Oct 24. pii: S1535-6108(22)00502-5. [Epub ahead of print]

FOXA2 drives lineage plasticity and KIT pathway activation in neuroendocrine prostate cancer.

Ming Han, Fei Li, Yehan Zhang, Pengfei Dai, Juan He, Yunguang Li, Yiqin Zhu, Junke Zheng, Hai Huang, Fan Bai, Dong Gao.

  Prostate cancer adeno-to-neuroendocrine lineage transition has emerged as a mechanism of targeted therapeutic resistance. Identifying the direct molecular drivers and developing pharmacological strategies using clinical-grade inhibitors to overcome lineage transition-induced therapeutic resistance are imperative. Here, using single-cell multiomics analyses, we investigate the dynamics of cellular heterogeneity, transcriptome regulation, and microenvironmental factors in 107,201 cells from genetically engineered mouse prostate cancer samples with complete time series of tumor evolution seen in patients. We identify that FOXA2 orchestrates prostate cancer adeno-to-neuroendocrine lineage transition and that Foxa2 expression is significantly induced by androgen deprivation. Moreover, Foxa2 knockdown induces the reversal of adeno-to-neuroendocrine transition. The KIT pathway is directly regulated by FOXA2 and specifically activated in neuroendocrine prostate cancer (NEPC). Pharmacologic inhibition of KIT pathway significantly suppresses mouse and human NEPC tumor growth. These findings reveal that FOXA2 drives adeno-to-neuroendocrine lineage plasticity in prostate cancer and provides a potential pharmacological strategy for castration-resistant NEPC.

Keywords:  Foxa1; Foxa2; KIT; clinical-grade inhibitors; pharmacological strategy; prostate cancer lineage plasticity; single-cell multiomics; therapeutic resistance

DOI:  https://doi.org/10.1016/j.ccell.2022.10.011