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Rodríguez-Rodríguez R, Baena M, Zagmutt S, Paraiso WK, Reguera AC, Fadó R, Casals N. International Union of Basic and Clinical Pharmacology. CXIX. Fundamental insights and clinical relevance regarding the carnitine palmitoyltransferase family of enzymes. Pharmacol Rev 2025; 77:100051. [PMID: 40106976 DOI: 10.1016/j.pharmr.2025.100051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 02/14/2025] [Indexed: 03/22/2025] Open
Abstract
The carnitine palmitoyltransferases (CPTs) play a key role in controlling the oxidation of long-chain fatty acids and are potential therapeutic targets for diseases with a strong metabolic component, such as obesity, diabetes, and cancer. Four distinct proteins are CPT1A, CPT1B, CPT1C, and CPT2, differing in tissue expression and catalytic activity. CPT1s are finely regulated by malonyl-CoA, a metabolite whose intracellular levels reflect the cell's nutritional state. Although CPT1C does not exhibit significant catalytic activity, it is capable of modulating the functioning of other neuronal proteins. Structurally, all CPTs share a Y-shaped catalytic tunnel that allows the entry of 2 substrates and accommodation of the acyl group in a hydrophobic pocket. Several molecules targeting these enzymes have been described, some showing potential in normalizing blood glucose levels in diabetic patients, and others that, through a central mechanism, are anorexigenic and enhance energy expenditure. However, given the critical roles that CPTs play in certain tissues, such as the heart, liver, and brain, it is essential to fully understand the differences between the various isoforms. We analyze in detail the structure of these proteins, their cellular and physiological functions, and their potential as therapeutic targets in diseases such as obesity, diabetes, and cancer. We also describe drugs identified to date as having inhibitory or activating capabilities for these proteins. This knowledge will support the design of new drugs specific to each isoform, and the development of nanomedicines that can selectively target particular tissues or cells. SIGNIFICANCE STATEMENT: Carnitine palmitoyltransferase (CPT) proteins, as gatekeepers of fatty acid oxidation, have great potential as pharmacological targets to treat metabolic diseases like obesity, diabetes, and cancer. In recent years, significant progress has been made in understanding the 3-dimensional structure of CPTs and their pathophysiological functions. A deeper understanding of the differences between the various CPT family members will enable the design of selective drugs and therapeutic approaches with fewer side effects.
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Affiliation(s)
- Rosalía Rodríguez-Rodríguez
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain.
| | - Miguel Baena
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, Spain
| | - Sebastián Zagmutt
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, Spain
| | - West Kristian Paraiso
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, Spain
| | - Ana Cristina Reguera
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, Spain
| | - Rut Fadó
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, Spain
| | - Núria Casals
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain.
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Zhu Y, Chen S, Su H, Meng Y, Zang C, Ning P, Hu L, Shao H. CPT1A-mediated MFF succinylation promotes stemness maintenance in ovarian cancer stem cells. Commun Biol 2025; 8:250. [PMID: 39956875 PMCID: PMC11830779 DOI: 10.1038/s42003-025-07720-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 02/11/2025] [Indexed: 02/18/2025] Open
Abstract
Cancer stem cells (CSCs) play crucial roles in cancer progression, immune evasion, drug resistance, and recurrence. Understanding the mechanisms behind CSCs generation and stemness maintenance is vital for early cancer diagnosis and treatment. Here, we unveil that carnitine palmitoyltransferase 1A (CPT1A) is highly expressed in ovarian cancer stem cells (OCSCs) and is essential for maintaining stemness by regulating lipid desaturation. Studies confirmed that CPT1A enhances SREBP1 activation, upregulating SCD1 expression, and promoting lipid desaturation in OCSCs. Mechanistic studies reveal that CPT1A promotes succinylation of mitochondrial fission factor (MFF) through its lysine succinyltransferase (LSTase) activity, crucial for mitochondria-associated membranes formation and SREBP1 activation. Inhibiting CPT1A's LSTase activity with Glyburide reduces OCSCs' stemness and enhances cisplatin's anti-tumor effects against ovarian cancer in vitro and in vivo. Together, our studies highlight the significance of CPT1A's LSTase activity in maintaining OCSCs' stemness, offering potential targets and therapeutic strategies for ovarian cancer treatment.
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Affiliation(s)
- Yaqin Zhu
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Shuting Chen
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Hong Su
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Yaning Meng
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Chen Zang
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Panjiao Ning
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Lele Hu
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China
| | - Huanjie Shao
- College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi, China.
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Merchant S, Paul A, Reyes A, Cassidy D, Leach A, Kim D, Muh S, Grabowski G, Hoxhaj G, Zhao Z, Morrison SJ. Different effects of fatty acid oxidation on hematopoietic stem cells based on age and diet. Cell Stem Cell 2025; 32:263-275.e5. [PMID: 39708796 DOI: 10.1016/j.stem.2024.11.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Revised: 09/19/2024] [Accepted: 11/25/2024] [Indexed: 12/23/2024]
Abstract
Fatty acid oxidation is of uncertain importance in most stem cells. We show by 14C-palmitate tracing and metabolomic analysis that hematopoietic stem/progenitor cells (HSPCs) engage in long-chain fatty acid oxidation that depends upon carnitine palmitoyltransferase 1a (CPT1a) and hydroxyacyl-CoA dehydrogenase (HADHA) enzymes. CPT1a or HADHA deficiency had little or no effect on HSPCs or hematopoiesis in young adult mice. Young HSPCs had the plasticity to oxidize other substrates, including glutamine, and compensated for loss of fatty acid oxidation by decreasing pyruvate dehydrogenase phosphorylation, which should increase function. This metabolic plasticity declined as mice aged, when CPT1a or HADHA deficiency altered hematopoiesis and impaired hematopoietic stem cell (HSC) function upon serial transplantation. A high-fat diet increased fatty acid oxidation and reduced HSC function. This was rescued by CPT1a or HADHA deficiency, demonstrating that increased fatty acid oxidation can undermine HSC function. Long-chain fatty acid oxidation is thus dispensable in young HSCs but necessary during aging and deleterious with a high-fat diet.
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Affiliation(s)
- Salma Merchant
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Animesh Paul
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Amanda Reyes
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Daniel Cassidy
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Ashley Leach
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Dohun Kim
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Sarah Muh
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Gerik Grabowski
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Gerta Hoxhaj
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Zhiyu Zhao
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Sean J Morrison
- Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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Qiu J, Yue F, Kim KH, Chen X, Khedr MA, Chen J, Gu L, Ren J, Ferreira CR, Ellis J, Kuang S. Overexpression of CPT1A disrupts the maintenance and regenerative function of muscle stem cells. FASEB J 2024; 38:e70071. [PMID: 39382025 PMCID: PMC11486317 DOI: 10.1096/fj.202400947r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 09/02/2024] [Accepted: 09/11/2024] [Indexed: 10/10/2024]
Abstract
The skeletal muscle satellite cells (SCs) mediate regeneration of myofibers upon injury. As they switch from maintenance (quiescence) to regeneration, their relative reliance on glucose and fatty acid metabolism alters. To explore the contribution of mitochondrial fatty acid oxidation (FAO) pathway to SCs and myogenesis, we examined the role of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO. CPT1A is highly expressed in quiescent SCs (QSCs) compared with activated and proliferating SCs, and its expression level decreases during myogenic differentiation. Myod1Cre-driven overexpression (OE) of Cpt1a in embryonic myoblasts (Cpt1aMTG) reduces muscle weight, grip strength, and contractile force without affecting treadmill endurance of adult mice. Adult Cpt1aMTG mice have reduced number of SC, impairing muscle regeneration and promoting lipid infiltration. Similarly, Pax7CreER-driven, tamoxifen-inducible Cpt1a-OE in QSCs of adult muscles (Cpt1aPTG) leads to depletion of SCs and compromises muscle regeneration. The reduced proliferation of Cpt1a-OE SCs is associated with elevated level of acyl-carnitine, and acyl-carnitine treatment impedes proliferation of wildtype SCs. These findings indicate that aberrant level of CPT1A elevates acyl-carnitine to impair the maintenance, proliferation and regenerative function of SCs.
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Affiliation(s)
- Jiamin Qiu
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
- These authors contributed equally to this work
| | - Feng Yue
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
- Department of Animal Sciences, University of Florida, Gainesville, FL 32611, USA
- These authors contributed equally to this work
| | - Kun Ho Kim
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Xiyue Chen
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
| | | | - Jingjuan Chen
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Lijie Gu
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Junxiao Ren
- Department of Animal Sciences, University of Florida, Gainesville, FL 32611, USA
| | - Christina R. Ferreira
- Purdue Metabolite Profiling Facility, Purdue University, West, Lafayette, IN 47907, USA
| | - Jessica Ellis
- Department of Physiology and East Carolina Diabetes and Obesity Institute, Brody School of Medicine at East Carolina University Greenville, NC 27834, USA
| | - Shihuan Kuang
- Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA
- Purdue University Institute for Cancer Research, West Lafayette, IN 47907, USA
- Departments of Orthopaedic Surgery, Duke University School of Medicine, Durham, NC 27710, USA
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Özgüldez HÖ, Bulut-Karslioğlu A. Dormancy, Quiescence, and Diapause: Savings Accounts for Life. Annu Rev Cell Dev Biol 2024; 40:25-49. [PMID: 38985838 DOI: 10.1146/annurev-cellbio-112122-022528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/12/2024]
Abstract
Life on Earth has been through numerous challenges over eons and, one way or another, has always triumphed. From mass extinctions to more daily plights to find food, unpredictability is everywhere. The adaptability of life-forms to ever-changing environments is the key that confers life's robustness. Adaptability has become synonymous with Darwinian evolution mediated by heritable genetic changes. The extreme gene-centric view, while being of central significance, at times has clouded our appreciation of the cell as a self-regulating entity informed of, and informing, the genetic data. An essential element that powers adaptability is the ability to regulate cell growth. In this review, we provide an extensive overview of growth regulation spanning species, tissues, and regulatory mechanisms. We aim to highlight the commonalities, as well as differences, of these phenomena and their molecular regulators. Finally, we curate open questions and areas for further exploration.
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Affiliation(s)
- Hatice Özge Özgüldez
- Stem Cell Chromatin Group, Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany;
| | - Aydan Bulut-Karslioğlu
- Stem Cell Chromatin Group, Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany;
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Rajan A, Fame RM. Brain development and bioenergetic changes. Neurobiol Dis 2024; 199:106550. [PMID: 38849103 PMCID: PMC11495523 DOI: 10.1016/j.nbd.2024.106550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 05/29/2024] [Accepted: 06/01/2024] [Indexed: 06/09/2024] Open
Abstract
Bioenergetics describe the biochemical processes responsible for energy supply in organisms. When these changes become dysregulated in brain development, multiple neurodevelopmental diseases can occur, implicating bioenergetics as key regulators of neural development. Historically, the discovery of disease processes affecting individual stages of brain development has revealed critical roles that bioenergetics play in generating the nervous system. Bioenergetic-dependent neurodevelopmental disorders include neural tube closure defects, microcephaly, intellectual disability, autism spectrum disorders, epilepsy, mTORopathies, and oncogenic processes. Developmental timing and cell-type specificity of these changes determine the long-term effects of bioenergetic disease mechanisms on brain form and function. Here, we discuss key metabolic regulators of neural progenitor specification, neuronal differentiation (neurogenesis), and gliogenesis. In general, transitions between glycolysis and oxidative phosphorylation are regulated in early brain development and in oncogenesis, and reactive oxygen species (ROS) and mitochondrial maturity play key roles later in differentiation. We also discuss how bioenergetics interface with the developmental regulation of other key neural elements, including the cerebrospinal fluid brain environment. While questions remain about the interplay between bioenergetics and brain development, this review integrates the current state of known key intersections between these processes in health and disease.
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Affiliation(s)
- Arjun Rajan
- Developmental Biology Graduate Program, Stanford University, Stanford, CA 94305, USA
| | - Ryann M Fame
- Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.
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Xing L, Huttner WB, Namba T. Role of cell metabolism in the pathophysiology of brain size-associated neurodevelopmental disorders. Neurobiol Dis 2024; 199:106607. [PMID: 39029564 DOI: 10.1016/j.nbd.2024.106607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 07/13/2024] [Accepted: 07/15/2024] [Indexed: 07/21/2024] Open
Abstract
Cell metabolism is a key regulator of human neocortex development and evolution. Several lines of evidence indicate that alterations in neural stem/progenitor cell (NPC) metabolism lead to abnormal brain development, particularly brain size-associated neurodevelopmental disorders, such as microcephaly. Abnormal NPC metabolism causes impaired cell proliferation and thus insufficient expansion of NPCs for neurogenesis. Therefore, the production of neurons, which is a major determinant of brain size, is decreased and the size of the brain, especially the size of the neocortex, is significantly reduced. This review discusses recent progress understanding NPC metabolism, focusing in particular on glucose metabolism, fatty acid metabolism and amino acid metabolism (e.g., glutaminolysis and serine metabolism). We provide an overview of the contributions of these metabolic pathways to brain development and evolution, as well as to the etiology of neurodevelopmental disorders. Furthermore, we discuss the advantages and disadvantages of various experimental models to study cell metabolism in the developing brain.
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Affiliation(s)
- Lei Xing
- Department of Biological Sciences, University of Manitoba, Winnipeg, MB, Canada.
| | - Wieland B Huttner
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
| | - Takashi Namba
- Neuroscience Center, HiLIFE - Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; Department of Developmental Biology, Fujita Health University School of Medicine, Toyoake, Japan; International Center for Brain Science (ICBS), Fujita Health University, Toyoake, Japan.
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8
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Sánchez-Ramírez E, Ung TPL, Stringari C, Aguilar-Arnal L. Emerging Functional Connections Between Metabolism and Epigenetic Remodeling in Neural Differentiation. Mol Neurobiol 2024; 61:6688-6707. [PMID: 38340204 PMCID: PMC11339152 DOI: 10.1007/s12035-024-04006-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 01/30/2024] [Indexed: 02/12/2024]
Abstract
Stem cells possess extraordinary capacities for self-renewal and differentiation, making them highly valuable in regenerative medicine. Among these, neural stem cells (NSCs) play a fundamental role in neural development and repair processes. NSC characteristics and fate are intricately regulated by the microenvironment and intracellular signaling. Interestingly, metabolism plays a pivotal role in orchestrating the epigenome dynamics during neural differentiation, facilitating the transition from undifferentiated NSC to specialized neuronal and glial cell types. This intricate interplay between metabolism and the epigenome is essential for precisely regulating gene expression patterns and ensuring proper neural development. This review highlights the mechanisms behind metabolic regulation of NSC fate and their connections with epigenetic regulation to shape transcriptional programs of stemness and neural differentiation. A comprehensive understanding of these molecular gears appears fundamental for translational applications in regenerative medicine and personalized therapies for neurological conditions.
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Affiliation(s)
- Edgar Sánchez-Ramírez
- Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Thi Phuong Lien Ung
- Laboratory for Optics and Biosciences, Ecole Polytechnique, CNRS, INSERM, Institut Polytechnique de Paris, Palaiseau, France
| | - Chiara Stringari
- Laboratory for Optics and Biosciences, Ecole Polytechnique, CNRS, INSERM, Institut Polytechnique de Paris, Palaiseau, France
| | - Lorena Aguilar-Arnal
- Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
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Madsen S, Delgado AC, Cadilhac C, Maillard V, Battiston F, Igelbüscher CM, De Neck S, Magrinelli E, Jabaudon D, Telley L, Doetsch F, Knobloch M. A fluorescent perilipin 2 knock-in mouse model reveals a high abundance of lipid droplets in the developing and adult brain. Nat Commun 2024; 15:5489. [PMID: 38942786 PMCID: PMC11213871 DOI: 10.1038/s41467-024-49449-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 06/03/2024] [Indexed: 06/30/2024] Open
Abstract
Lipid droplets (LDs) are dynamic lipid storage organelles. They are tightly linked to metabolism and can exert protective functions, making them important players in health and disease. Most LD studies in vivo rely on staining methods, providing only a snapshot. We therefore developed a LD-reporter mouse by labelling the endogenous LD coat protein perilipin 2 (PLIN2) with tdTomato, enabling staining-free fluorescent LD visualisation in living and fixed tissues and cells. Here we validate this model under standard and high-fat diet conditions and demonstrate that LDs are highly abundant in various cell types in the healthy brain, including neurons, astrocytes, ependymal cells, neural stem/progenitor cells and microglia. Furthermore, we also show that LDs are abundant during brain development and can be visualized using live imaging of embryonic slices. Taken together, our tdTom-Plin2 mouse serves as a novel tool to study LDs and their dynamics under both physiological and diseased conditions in all tissues expressing Plin2.
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Affiliation(s)
- Sofia Madsen
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | | | - Christelle Cadilhac
- Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland
| | - Vanille Maillard
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Fabrice Battiston
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | | | - Simon De Neck
- Institute of Veterinary Pathology, University of Zurich, Zurich, Switzerland
| | - Elia Magrinelli
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | - Denis Jabaudon
- Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland
| | - Ludovic Telley
- Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
| | | | - Marlen Knobloch
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland.
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Molloy JW, Barry D. The interplay between glucose and ketone bodies in neural stem cell metabolism. J Neurosci Res 2024; 102:e25342. [PMID: 38773878 DOI: 10.1002/jnr.25342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 04/29/2024] [Accepted: 05/05/2024] [Indexed: 05/24/2024]
Abstract
Glucose is the primary energy source for neural stem cells (NSCs), supporting their proliferation, differentiation, and quiescence. However, the high demand for glucose during brain development often exceeds its supply, leading to the utilization of alternative energy sources including ketone bodies. Ketone bodies, including β-hydroxybutyrate, are short-chain fatty acids produced through hepatic ketogenesis and play a crucial role in providing energy and the biosynthetic components for NSCs when required. The interplay between glucose and ketone metabolism influences NSC behavior and fate decisions, and disruptions in these metabolic pathways have been linked to neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Additionally, ketone bodies exert neuroprotective effects on NSCs and modulate cellular responses to oxidative stress, energy maintenance, deacetylation, and inflammation. As such, understanding the interdependence of glucose and ketone metabolism in NSCs is crucial to understanding their roles in NSC function and their implications for neurological conditions. This article reviews the mechanisms of glucose and ketone utilization in NSCs, their impact on NSC function, and the therapeutic potential of targeting these metabolic pathways in neurological disorders.
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Affiliation(s)
- Joseph W Molloy
- Discipline of Anatomy, School of Medicine, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, Dublin, Ireland
| | - Denis Barry
- Discipline of Anatomy, School of Medicine, Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, Dublin, Ireland
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11
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Song YF, Wang LJ, Luo Z, Hogstrand C, Lai XH, Zheng FF. Moderate replacement of fish oil with palmitic acid-stimulated mitochondrial fusion promotes β-oxidation by Mfn2 interacting with Cpt1α via its GTPase-domain. J Nutr Biochem 2024; 126:109559. [PMID: 38158094 DOI: 10.1016/j.jnutbio.2023.109559] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 12/22/2023] [Accepted: 12/26/2023] [Indexed: 01/03/2024]
Abstract
The mitochondrial matrix serves as the principal locale for the process of fatty acids (FAs) β-oxidation. Preserving the integrity and homeostasis of mitochondria, which is accomplished through ongoing fusion and fission events, is of paramount importance for the effective execution of FAs β-oxidation. There has been no investigation to date into whether and how mitochondrial fusion directly enhances FAs β-oxidation. The underlying mechanism of a balanced FAs ratio favoring hepatic lipid homeostasis remains largely unclear. To address such gaps, the present study was conducted to investigate the mechanism through which a balanced dietary FAs ratio enhances hepatic FAs β-oxidation. The investigation specifically focused on the involvement of Mfn2-mediated mitochondrial fusion in the regulation of Cpt1α in this process. In the present study, the yellow catfish (Pelteobagrus fulvidraco), recognized as a model organism for lipid metabolism, were subjected to eight weeks of in vivo feeding with six distinct diets featuring varying FAs ratios. Additionally, in vitro experiments were conducted to inhibit Mfn2-mediated mitochondrial fusion in isolated hepatocytes, achieved through the transfection of hepatocytes with si-mfn2. Further, deletion mutants for both Mfn2 and Cpt1α were constructed to elucidate the critical regions responsible for the interactions between these two proteins within the system. The key findings were: (1) Substituting palmitic acid (PA) for fish oil (FO) proved to be enhanced in reducing hepatic lipid accumulation. This beneficial effect was primarily attributed to the activation of mitochondrial FAs β-oxidation; (2) The balanced replacement of PA stimulated Mfn2-mediated mitochondrial fusion by diminishing Mfn2 ubiquitination, thereby enhancing its protein retention within the mitochondria; (3) Mfn2-mediated mitochondrial fusion promoted FAs β-oxidation through direct interaction between Mfn2 and Cpt1α via its GTPase-domains, which is essential for the maintenance of Cpt1 activity. Notably, the present research results unveil a previously undisclosed mechanism wherein Mfn2-mediated mitochondrial fusion promotes FAs β-oxidation by directly augmenting the capacity for FA transport into mitochondria (MT), in addition to expanding the mitochondrial matrix. This underscores the pivotal role of mitochondrial fusion in preserving hepatic lipid homeostasis. The present results further confirm that these mechanisms are evolutionarily conserved, extending their relevance from fish to mammals.
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Affiliation(s)
- Yu-Feng Song
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, China.
| | - Ling-Jiao Wang
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, China
| | - Zhi Luo
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Christer Hogstrand
- Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, London, UK
| | - Xiao-Hong Lai
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, China
| | - Fei-Fei Zheng
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, China
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12
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Weiliang W, Yinghao R, Weiliang H, Xiaobin Z, Chenglong Y, Weimiao A, Fei X, Fengpeng W. Identification of hub genes significantly linked to tuberous sclerosis related-epilepsy and lipid metabolism via bioinformatics analysis. Front Neurol 2024; 15:1354062. [PMID: 38419709 PMCID: PMC10899687 DOI: 10.3389/fneur.2024.1354062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 01/29/2024] [Indexed: 03/02/2024] Open
Abstract
Background Tuberous sclerosis complex (TSC) is one of the most common genetic causes of epilepsy. Identifying differentially expressed lipid metabolism related genes (DELMRGs) is crucial for guiding treatment decisions. Methods We acquired tuberous sclerosis related epilepsy (TSE) datasets, GSE16969 and GSE62019. Differential expression analysis identified 1,421 differentially expressed genes (DEGs). Intersecting these with lipid metabolism related genes (LMRGs) yielded 103 DELMRGs. DELMRGs underwent enrichment analyses, biomarker selection, disease classification modeling, immune infiltration analysis, weighted gene co-expression network analysis (WGCNA) and AUCell analysis. Results In TSE datasets, 103 DELMRGs were identified. Four diagnostic biomarkers (ALOX12B, CBS, CPT1C, and DAGLB) showed high accuracy for epilepsy diagnosis, with an AUC value of 0.9592. Significant differences (p < 0.05) in Plasma cells, T cells regulatory (Tregs), and Macrophages M2 were observed between diagnostic groups. Microglia cells were highly correlated with lipid metabolism functions. Conclusions Our research unveiled potential DELMRGs (ALOX12B, CBS, CPT1C and DAGLB) in TSE, which may provide new ideas for studying the psathogenesis of epilepsy.
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Affiliation(s)
- Wang Weiliang
- Epilepsy Center, Xiamen Humanity Hospital Fujian Medical University, Xiamen, Fujian, China
| | - Ren Yinghao
- Department of Dermatology, Xiamen Humanity Hospital Fujian Medical University, Xiamen, Fujian, China
| | - Hou Weiliang
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, State Key Laboratory of Medical Neurobiology, Ministry of Education Frontiers Center for Brain Science and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Zhang Xiaobin
- Epilepsy Center, Xiamen Humanity Hospital Fujian Medical University, Xiamen, Fujian, China
| | - Yang Chenglong
- Department of Neurosurgery, The Cancer Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - An Weimiao
- Epilepsy Center, Xiamen Humanity Hospital Fujian Medical University, Xiamen, Fujian, China
| | - Xu Fei
- Department of Pharmacogenomics, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Wang Fengpeng
- Epilepsy Center, Xiamen Humanity Hospital Fujian Medical University, Xiamen, Fujian, China
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13
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Szrok-Jurga S, Turyn J, Hebanowska A, Swierczynski J, Czumaj A, Sledzinski T, Stelmanska E. The Role of Acyl-CoA β-Oxidation in Brain Metabolism and Neurodegenerative Diseases. Int J Mol Sci 2023; 24:13977. [PMID: 37762279 PMCID: PMC10531288 DOI: 10.3390/ijms241813977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/08/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
This review highlights the complex role of fatty acid β-oxidation in brain metabolism. It demonstrates the fundamental importance of fatty acid degradation as a fuel in energy balance and as an essential component in lipid homeostasis, brain aging, and neurodegenerative disorders.
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Affiliation(s)
- Sylwia Szrok-Jurga
- Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland; (J.T.); (A.H.)
| | - Jacek Turyn
- Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland; (J.T.); (A.H.)
| | - Areta Hebanowska
- Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland; (J.T.); (A.H.)
| | - Julian Swierczynski
- Institute of Nursing and Medical Rescue, State University of Applied Sciences in Koszalin, 75-582 Koszalin, Poland;
| | - Aleksandra Czumaj
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdansk, 80-211 Gdansk, Poland; (A.C.); (T.S.)
| | - Tomasz Sledzinski
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdansk, 80-211 Gdansk, Poland; (A.C.); (T.S.)
| | - Ewa Stelmanska
- Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland; (J.T.); (A.H.)
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14
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Scandella V, Petrelli F, Moore DL, Braun SMG, Knobloch M. Neural stem cell metabolism revisited: a critical role for mitochondria. Trends Endocrinol Metab 2023; 34:446-461. [PMID: 37380501 DOI: 10.1016/j.tem.2023.05.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/29/2023] [Accepted: 05/30/2023] [Indexed: 06/30/2023]
Abstract
Metabolism has emerged as a key regulator of stem cell behavior. Mitochondria are crucial metabolic organelles that are important for differentiated cells, yet considered less so for stem cells. However, recent studies have shown that mitochondria influence stem cell maintenance and fate decisions, inviting a revised look at this topic. In this review, we cover the current literature addressing the role of mitochondrial metabolism in mouse and human neural stem cells (NSCs) in the embryonic and adult brain. We summarize how mitochondria are implicated in fate regulation and how substrate oxidation affects NSC quiescence. We further explore single-cell RNA sequencing (scRNA-seq) data for metabolic signatures of adult NSCs, highlight emerging technologies reporting on metabolic signatures, and discuss mitochondrial metabolism in other stem cells.
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Affiliation(s)
- Valentina Scandella
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Francesco Petrelli
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
| | - Darcie L Moore
- Department of Neuroscience, University of Wisconsin-Madison, Madison, WI, USA
| | - Simon M G Braun
- Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
| | - Marlen Knobloch
- Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland.
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15
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Zhu Y, Wang Y, Li Y, Li Z, Kong W, Zhao X, Chen S, Yan L, Wang L, Tong Y, Shao H. Carnitine palmitoyltransferase 1A promotes mitochondrial fission by enhancing MFF succinylation in ovarian cancer. Commun Biol 2023; 6:618. [PMID: 37291333 PMCID: PMC10250469 DOI: 10.1038/s42003-023-04993-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 05/30/2023] [Indexed: 06/10/2023] Open
Abstract
Mitochondria are dynamic organelles that are important for cell growth and proliferation. Dysregulated mitochondrial dynamics are highly associated with the initiation and progression of various cancers, including ovarian cancer. However, the regulatory mechanism underlying mitochondrial dynamics is still not fully understood. Previously, our study showed that carnitine palmitoyltransferase 1A (CPT1A) is highly expressed in ovarian cancer cells and promotes the development of ovarian cancer. Here, we find that CPT1A regulates mitochondrial dynamics and promotes mitochondrial fission in ovarian cancer cells. Our study futher shows that CPT1A regulates mitochondrial fission and function through mitochondrial fission factor (MFF) to promote the growth and proliferation of ovarian cancer cells. Mechanistically, we show that CPT1A promotes succinylation of MFF at lysine 302 (K302), which protects against Parkin-mediated ubiquitin-proteasomal degradation of MFF. Finally, the study shows that MFF is highly expressed in ovarian cancer cells and that high MFF expression is associated with poor prognosis in patients with ovarian cancer. MFF inhibition significantly inhibits the progression of ovarian cancer in vivo. Overall, CPT1A regulates mitochondrial dynamics through MFF succinylation to promote the development of ovarian cancer. Moreover, our findings suggest that MFF is a potential therapeutic target for ovarian cancer.
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Affiliation(s)
- Yaqin Zhu
- National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, 710119, Xi'an, Shaanxi, China
| | - Yue Wang
- National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, 710119, Xi'an, Shaanxi, China
| | - Ying Li
- National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, 710119, Xi'an, Shaanxi, China
| | - Zhongqi Li
- National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, 710119, Xi'an, Shaanxi, China
| | - Wenhui Kong
- National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, 710119, Xi'an, Shaanxi, China
| | - Xiaoxuan Zhao
- National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, 710119, Xi'an, Shaanxi, China
| | - Shuting Chen
- National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, 710119, Xi'an, Shaanxi, China
| | - Liting Yan
- National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, 710119, Xi'an, Shaanxi, China
| | - Lenan Wang
- National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, 710119, Xi'an, Shaanxi, China
| | - Yunli Tong
- National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, 710119, Xi'an, Shaanxi, China
| | - Huanjie Shao
- National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shaanxi Normal University, 710119, Xi'an, Shaanxi, China.
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Murtaj V, Butti E, Martino G, Panina-Bordignon P. Endogenous neural stem cells characterization using omics approaches: Current knowledge in health and disease. Front Cell Neurosci 2023; 17:1125785. [PMID: 37091923 PMCID: PMC10113633 DOI: 10.3389/fncel.2023.1125785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 03/03/2023] [Indexed: 04/08/2023] Open
Abstract
Neural stem cells (NSCs), an invaluable source of neuronal and glial progeny, have been widely interrogated in the last twenty years, mainly to understand their therapeutic potential. Most of the studies were performed with cells derived from pluripotent stem cells of either rodents or humans, and have mainly focused on their potential in regenerative medicine. High-throughput omics technologies, such as transcriptomics, epigenetics, proteomics, and metabolomics, which exploded in the past decade, represent a powerful tool to investigate the molecular mechanisms characterizing the heterogeneity of endogenous NSCs. The transition from bulk studies to single cell approaches brought significant insights by revealing complex system phenotypes, from the molecular to the organism level. Here, we will discuss the current literature that has been greatly enriched in the “omics era”, successfully exploring the nature and function of endogenous NSCs and the process of neurogenesis. Overall, the information obtained from omics studies of endogenous NSCs provides a sharper picture of NSCs function during neurodevelopment in healthy and in perturbed environments.
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Affiliation(s)
- Valentina Murtaj
- Division of Neuroscience, San Raffaele Vita-Salute University, Milan, Italy
- Neuroimmunology, Division of Neuroscience, Institute of Experimental Neurology, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Erica Butti
- Neuroimmunology, Division of Neuroscience, Institute of Experimental Neurology, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Gianvito Martino
- Division of Neuroscience, San Raffaele Vita-Salute University, Milan, Italy
- Neuroimmunology, Division of Neuroscience, Institute of Experimental Neurology, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Paola Panina-Bordignon
- Division of Neuroscience, San Raffaele Vita-Salute University, Milan, Italy
- Neuroimmunology, Division of Neuroscience, Institute of Experimental Neurology, IRCCS Ospedale San Raffaele, Milan, Italy
- *Correspondence: Paola Panina-Bordignon
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17
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Abstract
Multiple types of neural progenitor cells (NPCs) contribute to the development of the neocortex, a brain region responsible for our higher cognitive abilities. Proliferative capacity of NPCs varies among NPC types, developmental stages, and species. The higher proliferative capacity of NPCs in the developing human neocortex is thought to be a major contributing factor why humans have the most expanded neocortex within primates. Recent studies have shed light on the importance of cell metabolism in the neocortical NPC proliferative capacity. Specifically, glutaminolysis, a metabolic pathway that converts glutamine to glutamate and then to α-ketoglutarate, has been shown to play a critical role in human NPCs, both in apical and basal progenitors. In this review, we summarize our current knowledge of NPC metabolism, focusing especially on glutaminolysis, and discuss the role of NPC metabolism in neocortical development, evolution, and neurodevelopmental disorders, providing a broader perspective on a newly emerging research field.
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Affiliation(s)
- Vasiliki Gkini
- Neuroscience Center, HiLIFE—Helsinki
Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Takashi Namba
- Neuroscience Center, HiLIFE—Helsinki
Institute of Life Science, University of Helsinki, Helsinki, Finland
- Takashi Namba, Neuroscience Center, HiLIFE
— Helsinki Institute of Life Science, University of Helsinki, PO 63,
Haartmaninkatu 8, Helsinki 00014, Finland.
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18
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Anitha A, Thanseem I, Iype M, Thomas SV. Mitochondrial dysfunction in cognitive neurodevelopmental disorders: Cause or effect? Mitochondrion 2023; 69:18-32. [PMID: 36621534 DOI: 10.1016/j.mito.2023.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 12/21/2022] [Accepted: 01/04/2023] [Indexed: 01/07/2023]
Abstract
Mitochondria have a crucial role in brain development and neurogenesis, both in embryonic and adult brains. Since the brain is the highest energy consuming organ, it is highly vulnerable to mitochondrial dysfunction. This has been implicated in a range of brain disorders including, neurodevelopmental conditions, psychiatric illnesses, and neurodegenerative diseases. Genetic variations in mitochondrial DNA (mtDNA), and nuclear DNA encoding mitochondrial proteins, have been associated with several cognitive disorders. However, it is not yet clear whether mitochondrial dysfunction is a primary cause of these conditions or a secondary effect. Our review article deals with this topic, and brings out recent advances in mitochondria-oriented therapies. Mitochondrial dysfunction could be involved in the pathogenesis of a subset of disorders involving cognitive impairment. In these patients, mitochondrial dysfunction could be the cause of the condition, rather than the consequence. There are vast areas in this topic that remains to be explored and elucidated.
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Affiliation(s)
- Ayyappan Anitha
- Dept. of Neurogenetics, Institute for Communicative and Cognitive Neurosciences (ICCONS), Shoranur, Palakkad 679 523, Kerala, India.
| | - Ismail Thanseem
- Dept. of Neurogenetics, Institute for Communicative and Cognitive Neurosciences (ICCONS), Shoranur, Palakkad 679 523, Kerala, India
| | - Mary Iype
- Dept. of Pediatric Neurology, Government Medical College, Thiruvananthapuram 695 011, Kerala, India; Dept. of Neurology, ICCONS, Thiruvananthapuram 695 033, Kerala, India
| | - Sanjeev V Thomas
- Dept. of Neurology, ICCONS, Thiruvananthapuram 695 033, Kerala, India
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19
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Mormone E, Iorio EL, Abate L, Rodolfo C. Sirtuins and redox signaling interplay in neurogenesis, neurodegenerative diseases, and neural cell reprogramming. Front Neurosci 2023; 17:1073689. [PMID: 36816109 PMCID: PMC9929468 DOI: 10.3389/fnins.2023.1073689] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 01/13/2023] [Indexed: 02/04/2023] Open
Abstract
Since the discovery of Neural Stem Cells (NSCs) there are still mechanism to be clarified, such as the role of mitochondrial metabolism in the regulation of endogenous adult neurogenesis and its implication in neurodegeneration. Although stem cells require glycolysis to maintain their stemness, they can perform oxidative phosphorylation and it is becoming more and more evident that mitochondria are central players, not only for ATP production but also for neuronal differentiation's steps regulation, through their ability to handle cellular redox state, intracellular signaling, epigenetic state of the cell, as well as the gut microbiota-brain axis, upon dietary influences. In this scenario, the 8-oxoguanine DNA glycosylase (OGG1) repair system would link mitochondrial DNA integrity to the modulation of neural differentiation. On the other side, there is an increasing interest in NSCs generation, from induced pluripotent stem cells, as a clinical model for neurodegenerative diseases (NDs), although this methodology still presents several drawbacks, mainly related to the reprogramming process. Indeed, high levels of reactive oxygen species (ROS), associated with telomere shortening, genomic instability, and defective mitochondrial dynamics, lead to pluripotency limitation and reprogramming efficiency's reduction. Moreover, while a physiological or moderate ROS increase serves as a signaling mechanism, to activate differentiation and suppress self-renewal, excessive oxidative stress is a common feature of NDs and aging. This ROS-dependent regulatory effect might be modulated by newly identified ROS suppressors, including the NAD+-dependent deacetylase enzymes family called Sirtuins (SIRTs). Recently, the importance of subcellular localization of NAD synthesis has been coupled to different roles for NAD in chromatin stability, DNA repair, circadian rhythms, and longevity. SIRTs have been described as involved in the control of both telomere's chromatin state and expression of nuclear gene involved in the regulation of mitochondrial gene expression, as well as in several NDs and aging. SIRTs are ubiquitously expressed in the mammalian brain, where they play important roles. In this review we summarize the current knowledge on how SIRTs-dependent modulation of mitochondrial metabolism could impact on neurogenesis and neurodegeneration, focusing mainly on ROS function and their role in SIRTs-mediated cell reprogramming and telomere protection.
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Affiliation(s)
- Elisabetta Mormone
- Unitá Produttiva per Terapie Avanzate, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy,*Correspondence: Elisabetta Mormone, ;
| | | | - Lucrezia Abate
- Unitá Produttiva per Terapie Avanzate, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Carlo Rodolfo
- Department of Biology, University of Rome Tor Vergata, Rome, Italy,Department of Paediatric Onco-Haematology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy,Carlo Rodolfo,
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20
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Zhao X, Zhang S, Sanders AR, Duan J. Brain Lipids and Lipid Droplet Dysregulation in Alzheimer's Disease and Neuropsychiatric Disorders. Complex Psychiatry 2023; 9:154-171. [PMID: 38058955 PMCID: PMC10697751 DOI: 10.1159/000535131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 11/06/2023] [Indexed: 12/08/2023] Open
Abstract
Background Lipids are essential components of the structure and for the function of brain cells. The intricate balance of lipids, including phospholipids, glycolipids, cholesterol, cholesterol ester, and triglycerides, is crucial for maintaining normal brain function. The roles of lipids and lipid droplets and their relevance to neurodegenerative and neuropsychiatric disorders (NPDs) remain largely unknown. Summary Here, we reviewed the basic role of lipid components as well as a specific lipid organelle, lipid droplets, in brain function, highlighting the potential impact of altered lipid metabolism in the pathogenesis of Alzheimer's disease (AD) and NDPs. Key Messages Brain lipid dysregulation plays a pivotal role in the pathogenesis and progression of neurodegenerative and NPDs including AD and schizophrenia. Understanding the cell type-specific mechanisms of lipid dysregulation in these diseases is crucial for identifying better diagnostic biomarkers and for developing therapeutic strategies aiming at restoring lipid homeostasis.
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Affiliation(s)
- Xiaojie Zhao
- Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL, USA
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA
| | - Siwei Zhang
- Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL, USA
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA
| | - Alan R. Sanders
- Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL, USA
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA
| | - Jubao Duan
- Center for Psychiatric Genetics, NorthShore University HealthSystem, Evanston, IL, USA
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA
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Petridi S, Dubal D, Rikhy R, van den Ameele J. Mitochondrial respiration and dynamics of in vivo neural stem cells. Development 2022; 149:285126. [PMID: 36445292 PMCID: PMC10112913 DOI: 10.1242/dev.200870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
Neural stem cells (NSCs) in the developing and adult brain undergo many different transitions, tightly regulated by extrinsic and intrinsic factors. While the role of signalling pathways and transcription factors is well established, recent evidence has also highlighted mitochondria as central players in NSC behaviour and fate decisions. Many aspects of cellular metabolism and mitochondrial biology change during NSC transitions, interact with signalling pathways and affect the activity of chromatin-modifying enzymes. In this Spotlight, we explore recent in vivo findings, primarily from Drosophila and mammalian model systems, about the role that mitochondrial respiration and morphology play in NSC development and function.
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Affiliation(s)
- Stavroula Petridi
- Department of Clinical Neurosciences and MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK
| | - Dnyanesh Dubal
- Department of Clinical Neurosciences and MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK.,Biology, Indian Institute of Science Education and Research, Homi Bhabha Road, Pashan, Pune 411008, India
| | - Richa Rikhy
- Biology, Indian Institute of Science Education and Research, Homi Bhabha Road, Pashan, Pune 411008, India
| | - Jelle van den Ameele
- Department of Clinical Neurosciences and MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge CB2 0XY, UK
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22
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Liu HX, Zhao H, Xi C, Li S, Ma LP, Lu X, Yan J, Tian XL, Gao L, Tian M, Liu QJ. CPT1 Mediated Ionizing Radiation-Induced Intestinal Injury Proliferation via Shifting FAO Metabolism Pathway and Activating the ERK1/2 and JNK Pathway. Radiat Res 2022; 198:488-507. [PMID: 36351324 DOI: 10.1667/rade-21-00174.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 07/07/2022] [Indexed: 06/16/2023]
Abstract
The intestinal compensatory proliferative potential is a key influencing factor for susceptibility to radiation-induced intestinal injury. Studies indicated that the carnitine palmitoyltransferase 1 (CPT1) mediated fatty acid β-oxidation (FAO) plays a crucial role in promoting the survival and proliferation of tumor cells. Here, we aimed to explore the effect of 60Co gamma rays on CPT1 mediated FAO in the radiation-induced intestinal injury models, and investigate the role of CPT1 mediated FAO in the survival and proliferation of intestinal cells after irradiation. We detected the changed of FAO in the plasma and small intestine of Sprague Dawley (SD) rats at 24 h after 60Co gamma irradiation (0, 5 and 10 Gy), using target metabolomics, qRT-PCR, immunohistochemistry (IHC), western blot (WB) and related enzymatic activity kits. We then analyzed the FAO changes in radiation-induced intestinal injury models regardless of ex vivo (mice enteroids), or in vitro (normal human intestinal epithelial cell lines, HIEC-6). HIEC-6 cells were transduced with lentivirus vector GV392 and treated with puromycin for obtaining CPT1 stable knockout cell lines, named CPT1 KO. CPT1 enzymatic activities of HIEC-6 cells and mice enteroids were also inhibited by pharmaceutical inhibitor ST1326 and Etomoxir (ETO), to study the function of CPT1 in the survival and proliferation of HIEC-6 cells after 60Co gamma irradiation. We found that CPT1 mediated FAO was altered in the small intestine of the SD rats after irradiation, especially, the expression level and enzymatic activity of CPT1 were significantly increased. Similarly, the expression levels of CPT1 were also remarkably enhanced in mice enteroids and HIEC-6 cells after irradiation. CPT1 inhibition decreased the proliferation of the HIEC-6 cells and mice enteroids after irradiation partially by reducing the extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways activation, CPT1 inhibition also reduced the proliferation of mice enteroids after irradiation partially by down-regulating the Wnt/β-catenin signaling activity. In conclusion, our study indicated that CPT1 plays a crucial role in promoting intestinal epithelial cell proliferation after irradiation.
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Affiliation(s)
- Hai-Xiang Liu
- China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Hua Zhao
- China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Cong Xi
- China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Shuang Li
- China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Li-Ping Ma
- China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Xue Lu
- China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Juan Yan
- China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Xue-Lei Tian
- China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Ling Gao
- China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Mei Tian
- China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
| | - Qing-Jie Liu
- China CDC Key Laboratory of Radiological Protection and Nuclear Emergency, National Institute for Radiological Protection, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China
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Angelopoulos I, Gakis G, Birmpas K, Kyrousi C, Habeos EE, Kaplani K, Lygerou Z, Habeos I, Taraviras S. Metabolic regulation of the neural stem cell fate: Unraveling new connections, establishing new concepts. Front Neurosci 2022; 16:1009125. [PMID: 36340763 PMCID: PMC9634649 DOI: 10.3389/fnins.2022.1009125] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 10/03/2022] [Indexed: 11/30/2022] Open
Abstract
The neural stem cell niche is a key regulator participating in the maintenance, regeneration, and repair of the brain. Within the niche neural stem cells (NSC) generate new neurons throughout life, which is important for tissue homeostasis and brain function. NSCs are regulated by intrinsic and extrinsic factors with cellular metabolism being lately recognized as one of the most important ones, with evidence suggesting that it may serve as a common signal integrator to ensure mammalian brain homeostasis. The aim of this review is to summarize recent insights into how metabolism affects NSC fate decisions in adult neural stem cell niches, with occasional referencing of embryonic neural stem cells when it is deemed necessary. Specifically, we will highlight the implication of mitochondria as crucial regulators of NSC fate decisions and the relationship between metabolism and ependymal cells. The link between primary cilia dysfunction in the region of hypothalamus and metabolic diseases will be examined as well. Lastly, the involvement of metabolic pathways in ependymal cell ciliogenesis and physiology regulation will be discussed.
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Affiliation(s)
| | - Georgios Gakis
- Department of Physiology, Medical School, University of Patras, Patras, Greece
| | - Kyriakos Birmpas
- Department of Physiology, Medical School, University of Patras, Patras, Greece
| | - Christina Kyrousi
- First Department of Psychiatry, Medical School, National and Kapodistrian University of Athens, Eginition Hospital, Athens, Greece
- University Mental Health, Neurosciences and Precision Medicine Research Institute “Costas Stefanis”, Athens, Greece
| | - Evagelia Eva Habeos
- Department of Physiology, Medical School, University of Patras, Patras, Greece
| | - Konstantina Kaplani
- Department of Physiology, Medical School, University of Patras, Patras, Greece
| | - Zoi Lygerou
- Department of General Biology, School of Medicine, University of Patras, Patras, Greece
| | - Ioannis Habeos
- Division of Endocrinology, Department of Internal Medicine, University of Patras, Patras, Greece
| | - Stavros Taraviras
- Department of Physiology, Medical School, University of Patras, Patras, Greece
- *Correspondence: Stavros Taraviras,
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24
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Puca F, Fedele M, Rasio D, Battista S. Role of Diet in Stem and Cancer Stem Cells. Int J Mol Sci 2022; 23:ijms23158108. [PMID: 35897685 PMCID: PMC9330301 DOI: 10.3390/ijms23158108] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 07/20/2022] [Accepted: 07/21/2022] [Indexed: 11/16/2022] Open
Abstract
Diet and lifestyle factors greatly affect health and susceptibility to diseases, including cancer. Stem cells’ functions, including their ability to divide asymmetrically, set the rules for tissue homeostasis, contribute to health maintenance, and represent the entry point of cancer occurrence. Stem cell properties result from the complex integration of intrinsic, extrinsic, and systemic factors. In this context, diet-induced metabolic changes can have a profound impact on stem cell fate determination, lineage specification and differentiation. The purpose of this review is to provide a comprehensive description of the multiple “non-metabolic” effects of diet on stem cell functions, including little-known effects such as those on liquid-liquid phase separation and on non-random chromosome segregation (asymmetric division). A deep understanding of the specific dietetic requirements of normal and cancer stem cells may pave the way for the development of nutrition-based targeted therapeutic approaches to improve regenerative and anticancer therapies.
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Affiliation(s)
- Francesca Puca
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 78705, USA;
- Department of Oncology, IRBM Science Park SpA, 00071 Pomezia, Italy
| | - Monica Fedele
- Institute for Experimental Endocrinology and Oncology (IEOS), National Research Council (CNR), 80131 Naples, Italy;
| | - Debora Rasio
- Department of Clinical and Molecular Medicine, La Sapienza University, 00185 Rome, Italy;
| | - Sabrina Battista
- Institute for Experimental Endocrinology and Oncology (IEOS), National Research Council (CNR), 80131 Naples, Italy;
- Correspondence:
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25
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Xie Z, Bankaitis VA. Phosphatidylinositol transfer protein/planar cell polarity axis regulates neocortical morphogenesis by supporting interkinetic nuclear migration. Cell Rep 2022; 39:110869. [PMID: 35649377 PMCID: PMC9230501 DOI: 10.1016/j.celrep.2022.110869] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 03/08/2022] [Accepted: 05/05/2022] [Indexed: 11/29/2022] Open
Abstract
The neocortex expands explosively during embryonic development. The earliest populations of neural stem cells (NSCs) form a thin pseudostratified epithelium whose contour determines that of the adult neocortex. Neocortical complexity is accompanied by disproportional expansion of the NSC layer in its tangential dimension to increase tissue surface area. How such disproportional expansion is controlled remains unknown. We demonstrate that a phosphatidylinositol transfer protein (PITP)/non-canonical Wnt planar cell polarity (ncPCP) signaling axis promotes tangential expansion of developing neocortex. PITP signaling supports trafficking of specific ncPCP receptors from the NSC Golgi system to potentiate actomyosin activity important for cell-cycle-dependent interkinetic nuclear migration (IKNM). In turn, IKNM promotes lateral dispersion of newborn NSCs and tangential growth of the cerebral wall. These findings clarify functional roles for IKNM in NSC biology and identify tissue dysmorphogenesis resulting from impaired IKNM as a factor in autism risk, developmental brain disabilities, and neural tube birth defects. Xie and Bankaitis report that a phosphatidylinositol transfer protein/non-canonical planar cell polarity signaling axis supports interkinetic nuclear migration by promoting trafficking of specific non-canonical planar cell polarity receptors from the Golgi system to the plasma membrane, activating actomyosin, and supporting lateral expansion of the neocortex via a convergent extension mechanism.
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Affiliation(s)
- Zhigang Xie
- Department of Molecular & Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843, USA.
| | - Vytas A Bankaitis
- Department of Molecular & Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843, USA; Department of Biochemistry & Biophysics, Texas A&M University, College Station, TX 77843, USA; Department of Chemistry, Texas A&M University, College Station, TX 77843, USA.
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26
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Romero-Morales AI, Gama V. Revealing the Impact of Mitochondrial Fitness During Early Neural Development Using Human Brain Organoids. Front Mol Neurosci 2022; 15:840265. [PMID: 35571368 PMCID: PMC9102998 DOI: 10.3389/fnmol.2022.840265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 04/04/2022] [Indexed: 11/13/2022] Open
Abstract
Mitochondrial homeostasis -including function, morphology, and inter-organelle communication- provides guidance to the intrinsic developmental programs of corticogenesis, while also being responsive to environmental and intercellular signals. Two- and three-dimensional platforms have become useful tools to interrogate the capacity of cells to generate neuronal and glia progeny in a background of metabolic dysregulation, but the mechanistic underpinnings underlying the role of mitochondria during human neurogenesis remain unexplored. Here we provide a concise overview of cortical development and the use of pluripotent stem cell models that have contributed to our understanding of mitochondrial and metabolic regulation of early human brain development. We finally discuss the effects of mitochondrial fitness dysregulation seen under stress conditions such as metabolic dysregulation, absence of developmental apoptosis, and hypoxia; and the avenues of research that can be explored with the use of brain organoids.
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Affiliation(s)
| | - Vivian Gama
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, United States
- Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, United States
- Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, United States
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27
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Islimye E, Girard V, Gould AP. Functions of Stress-Induced Lipid Droplets in the Nervous System. Front Cell Dev Biol 2022; 10:863907. [PMID: 35493070 PMCID: PMC9047859 DOI: 10.3389/fcell.2022.863907] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 03/22/2022] [Indexed: 12/12/2022] Open
Abstract
Lipid droplets are highly dynamic intracellular organelles that store neutral lipids such as cholesteryl esters and triacylglycerols. They have recently emerged as key stress response components in many different cell types. Lipid droplets in the nervous system are mostly observed in vivo in glia, ependymal cells and microglia. They tend to become more numerous in these cell types and can also form in neurons as a consequence of ageing or stresses involving redox imbalance and lipotoxicity. Abundant lipid droplets are also a characteristic feature of several neurodegenerative diseases. In this minireview, we take a cell-type perspective on recent advances in our understanding of lipid droplet metabolism in glia, neurons and neural stem cells during health and disease. We highlight that a given lipid droplet subfunction, such as triacylglycerol lipolysis, can be physiologically beneficial or harmful to the functions of the nervous system depending upon cellular context. The mechanistic understanding of context-dependent lipid droplet functions in the nervous system is progressing apace, aided by new technologies for probing the lipid droplet proteome and lipidome with single-cell type precision.
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28
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San Martín A, Arce-Molina R, Aburto C, Baeza-Lehnert F, Barros LF, Contreras-Baeza Y, Pinilla A, Ruminot I, Rauseo D, Sandoval PY. Visualizing physiological parameters in cells and tissues using genetically encoded indicators for metabolites. Free Radic Biol Med 2022; 182:34-58. [PMID: 35183660 DOI: 10.1016/j.freeradbiomed.2022.02.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/08/2022] [Accepted: 02/10/2022] [Indexed: 02/07/2023]
Abstract
The study of metabolism is undergoing a renaissance. Since the year 2002, over 50 genetically-encoded fluorescent indicators (GEFIs) have been introduced, capable of monitoring metabolites with high spatial/temporal resolution using fluorescence microscopy. Indicators are fusion proteins that change their fluorescence upon binding a specific metabolite. There are indicators for sugars, monocarboxylates, Krebs cycle intermediates, amino acids, cofactors, and energy nucleotides. They permit monitoring relative levels, concentrations, and fluxes in living systems. At a minimum they report relative levels and, in some cases, absolute concentrations may be obtained by performing ad hoc calibration protocols. Proper data collection, processing, and interpretation are critical to take full advantage of these new tools. This review offers a survey of the metabolic indicators that have been validated in mammalian systems. Minimally invasive, these indicators have been instrumental for the purposes of confirmation, rebuttal and discovery. We envision that this powerful technology will foster metabolic physiology.
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Affiliation(s)
- A San Martín
- Centro de Estudios Científicos (CECs), Valdivia, Chile.
| | - R Arce-Molina
- Centro de Estudios Científicos (CECs), Valdivia, Chile
| | - C Aburto
- Centro de Estudios Científicos (CECs), Valdivia, Chile; Universidad Austral de Chile, Valdivia, Chile
| | | | - L F Barros
- Centro de Estudios Científicos (CECs), Valdivia, Chile
| | - Y Contreras-Baeza
- Centro de Estudios Científicos (CECs), Valdivia, Chile; Universidad Austral de Chile, Valdivia, Chile
| | - A Pinilla
- Centro de Estudios Científicos (CECs), Valdivia, Chile; Universidad Austral de Chile, Valdivia, Chile
| | - I Ruminot
- Centro de Estudios Científicos (CECs), Valdivia, Chile
| | - D Rauseo
- Centro de Estudios Científicos (CECs), Valdivia, Chile; Universidad Austral de Chile, Valdivia, Chile
| | - P Y Sandoval
- Centro de Estudios Científicos (CECs), Valdivia, Chile
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29
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Wani GA, Sprenger HG, Ndoci K, Chandragiri S, Acton RJ, Schatton D, Kochan SMV, Sakthivelu V, Jevtic M, Seeger JM, Müller S, Giavalisco P, Rugarli EI, Motori E, Langer T, Bergami M. Metabolic control of adult neural stem cell self-renewal by the mitochondrial protease YME1L. Cell Rep 2022; 38:110370. [PMID: 35172139 DOI: 10.1016/j.celrep.2022.110370] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 11/29/2021] [Accepted: 01/20/2022] [Indexed: 01/17/2023] Open
Abstract
The transition between quiescence and activation in neural stem and progenitor cells (NSPCs) is coupled with reversible changes in energy metabolism with key implications for lifelong NSPC self-renewal and neurogenesis. How this metabolic plasticity is ensured between NSPC activity states is unclear. We find that a state-specific rewiring of the mitochondrial proteome by the i-AAA peptidase YME1L is required to preserve NSPC self-renewal. YME1L controls the abundance of numerous mitochondrial substrates in quiescent NSPCs, and its deletion activates a differentiation program characterized by broad metabolic changes causing the irreversible shift away from a fatty-acid-oxidation-dependent state. Conditional Yme1l deletion in adult NSPCs in vivo results in defective self-renewal and premature differentiation, ultimately leading to NSPC pool depletion. Our results disclose an important role for YME1L in coordinating the switch between metabolic states of NSPCs and suggest that NSPC fate is regulated by compartmentalized changes in protein network dynamics.
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Affiliation(s)
- Gulzar A Wani
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
| | - Hans-Georg Sprenger
- Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931 Cologne, Germany
| | - Kristiano Ndoci
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
| | - Srikanth Chandragiri
- Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931 Cologne, Germany
| | - Richard James Acton
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
| | - Désirée Schatton
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
| | - Sandra M V Kochan
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
| | - Vignesh Sakthivelu
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
| | - Milica Jevtic
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
| | - Jens M Seeger
- Institute for Molecular Immunology, CECAD Research Center and University Hospital Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
| | - Stefan Müller
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany; Center for Molecular Medicine, Robert-Koch-Str. 21, 50931 Cologne, Germany
| | - Patrick Giavalisco
- Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931 Cologne, Germany
| | - Elena I Rugarli
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany; Center for Molecular Medicine, Robert-Koch-Str. 21, 50931 Cologne, Germany; Institute of Genetics, University of Cologne, Zülpicher Str. 47a, 50674 Cologne, Germany
| | - Elisa Motori
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany; Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931 Cologne, Germany
| | - Thomas Langer
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany; Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931 Cologne, Germany
| | - Matteo Bergami
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany; Center for Molecular Medicine, Robert-Koch-Str. 21, 50931 Cologne, Germany; Institute of Genetics, University of Cologne, Zülpicher Str. 47a, 50674 Cologne, Germany; University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 62, 50937 Cologne, Germany.
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30
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FASN-dependent de novo lipogenesis is required for brain development. Proc Natl Acad Sci U S A 2022; 119:2112040119. [PMID: 34996870 PMCID: PMC8764667 DOI: 10.1073/pnas.2112040119] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/23/2021] [Indexed: 01/24/2023] Open
Abstract
Fate and behavior of neural progenitor cells are tightly regulated during mammalian brain development. Metabolic pathways, such as glycolysis and oxidative phosphorylation, that are required for supplying energy and providing molecular building blocks to generate cells govern progenitor function. However, the role of de novo lipogenesis, which is the conversion of glucose into fatty acids through the multienzyme protein fatty acid synthase (FASN), for brain development remains unknown. Using Emx1Cre-mediated, tissue-specific deletion of Fasn in the mouse embryonic telencephalon, we show that loss of FASN causes severe microcephaly, largely due to altered polarity of apical, radial glia progenitors and reduced progenitor proliferation. Furthermore, genetic deletion and pharmacological inhibition of FASN in human embryonic stem cell-derived forebrain organoids identifies a conserved role of FASN-dependent lipogenesis for radial glia cell polarity in human brain organoids. Thus, our data establish a role of de novo lipogenesis for mouse and human brain development and identify a link between progenitor-cell polarity and lipid metabolism.
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31
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Guo N, McDermott KD, Shih YT, Zanga H, Ghosh D, Herber C, Meara WR, Coleman J, Zagouras A, Wong LP, Sadreyev R, Gonçalves JT, Sahay A. Transcriptional regulation of neural stem cell expansion in the adult hippocampus. eLife 2022; 11:e72195. [PMID: 34982030 PMCID: PMC8820733 DOI: 10.7554/elife.72195] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 01/03/2022] [Indexed: 12/11/2022] Open
Abstract
Experience governs neurogenesis from radial-glial neural stem cells (RGLs) in the adult hippocampus to support memory. Transcription factors (TFs) in RGLs integrate physiological signals to dictate self-renewal division mode. Whereas asymmetric RGL divisions drive neurogenesis during favorable conditions, symmetric divisions prevent premature neurogenesis while amplifying RGLs to anticipate future neurogenic demands. The identities of TFs regulating RGL symmetric self-renewal, unlike those that regulate RGL asymmetric self-renewal, are not known. Here, we show in mice that the TF Kruppel-like factor 9 (Klf9) is elevated in quiescent RGLs and inducible, deletion of Klf9 promotes RGL activation state. Clonal analysis and longitudinal intravital two-photon imaging directly demonstrate that Klf9 functions as a brake on RGL symmetric self-renewal. In vivo translational profiling of RGLs lacking Klf9 generated a molecular blueprint for RGL symmetric self-renewal that was characterized by upregulation of genetic programs underlying Notch and mitogen signaling, cell cycle, fatty acid oxidation, and lipogenesis. Together, these observations identify Klf9 as a transcriptional regulator of neural stem cell expansion in the adult hippocampus.
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Affiliation(s)
- Nannan Guo
- Center for Regenerative Medicine, Massachusetts General HospitalBostonUnited States
- Harvard Stem Cell InstituteCambridgeUnited States
- Department of Psychiatry, Massachusetts General Hospital, Harvard Medical SchoolBostonUnited States
- BROAD Institute of Harvard and MITCambridgeUnited States
| | - Kelsey D McDermott
- Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine; Dominick Purpura Department of Neuroscience, Albert Einstein College of MedicineBronxUnited States
| | - Yu-Tzu Shih
- Center for Regenerative Medicine, Massachusetts General HospitalBostonUnited States
- Harvard Stem Cell InstituteCambridgeUnited States
- Department of Psychiatry, Massachusetts General Hospital, Harvard Medical SchoolBostonUnited States
- BROAD Institute of Harvard and MITCambridgeUnited States
| | - Haley Zanga
- Center for Regenerative Medicine, Massachusetts General HospitalBostonUnited States
- Harvard Stem Cell InstituteCambridgeUnited States
- Department of Psychiatry, Massachusetts General Hospital, Harvard Medical SchoolBostonUnited States
- BROAD Institute of Harvard and MITCambridgeUnited States
| | - Debolina Ghosh
- Center for Regenerative Medicine, Massachusetts General HospitalBostonUnited States
- Harvard Stem Cell InstituteCambridgeUnited States
| | - Charlotte Herber
- Center for Regenerative Medicine, Massachusetts General HospitalBostonUnited States
- Harvard Stem Cell InstituteCambridgeUnited States
| | - William R Meara
- Center for Regenerative Medicine, Massachusetts General HospitalBostonUnited States
- Harvard Stem Cell InstituteCambridgeUnited States
| | - James Coleman
- Center for Regenerative Medicine, Massachusetts General HospitalBostonUnited States
- Harvard Stem Cell InstituteCambridgeUnited States
| | - Alexia Zagouras
- Center for Regenerative Medicine, Massachusetts General HospitalBostonUnited States
- Harvard Stem Cell InstituteCambridgeUnited States
| | - Lai Ping Wong
- Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical SchoolBostonUnited States
| | - Ruslan Sadreyev
- Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical SchoolBostonUnited States
| | - J Tiago Gonçalves
- Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine; Dominick Purpura Department of Neuroscience, Albert Einstein College of MedicineBronxUnited States
| | - Amar Sahay
- Center for Regenerative Medicine, Massachusetts General HospitalBostonUnited States
- Harvard Stem Cell InstituteCambridgeUnited States
- Department of Psychiatry, Massachusetts General Hospital, Harvard Medical SchoolBostonUnited States
- BROAD Institute of Harvard and MITCambridgeUnited States
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32
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Li H, Li S, Ren C, Gao C, Li N, Wang C, Wang L, Zhao W, Ji X, Jin K. Hypoxic postconditioning promotes neurogenesis by modulating the metabolism of neural stem cells after cerebral ischemia. Exp Neurol 2022; 347:113871. [PMID: 34563509 DOI: 10.1016/j.expneurol.2021.113871] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 08/25/2021] [Accepted: 09/20/2021] [Indexed: 12/30/2022]
Abstract
Ischemic stroke is one of the most lethal and severely disabling diseases that seriously affects human health and quality of life. The maintenance of self-renewal and differentiation of neural stem cells are closely related to metabolism. This study aimed to investigate whether hypoxic postconditioning (HPC) could promote neurogenesis after ischemic stroke, and to investigate the role of neuronal stem cell metabolism in HPC-induced neuroprotection. Male C57BL/6 mice were subjected to transient middle cerebral artery occlusion (MCAO), and HPC was performed for 3 h per day. Immunofluorescence staining was used to assess neurogenesis. The cell line NE-4C was used to elucidate the proliferation of neuronal stem cells in 21% O2 or 8% O2. HPC promoted the recovery of neurological function in mice on day 14. HPC promoted neuronal precursor proliferation in the subventricular zone (SVZ) on day 7 and enhanced neuronal precursor migration in the basal ganglia and cortex on day 14. Fatty acid oxidation (FAO) and glycolysis of neural stem cells in the SVZ changed after MCAO with or without HPC. HPC promoted the proliferation of NE-4C stem cells, decreased FAO and increased glycolysis. All these beneficial effects of HPC were ablated by the application of an FAO activator or a glycolysis inhibitor. In conclusion, cerebral ischemia modulated the FAO and glycolysis of neural stem cells. HPC promoted the proliferation and migration of neural stem cells after MCAO, and these effects may be related to the regulation of metabolism, including FAO and glycolysis.
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Affiliation(s)
- Haiyan Li
- Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Capital Medical University, Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing, China; Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing, China
| | - Sijie Li
- Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Capital Medical University, Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing, China; Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing, China
| | - Changhong Ren
- Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Capital Medical University, Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing, China; Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing, China
| | - Chen Gao
- Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing, China
| | - Ning Li
- Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Capital Medical University, Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing, China; Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing, China
| | - Chunxiu Wang
- Department of Evidence-based Medicine, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Lin Wang
- Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Capital Medical University, Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing, China; Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing, China
| | - Wenbo Zhao
- Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Capital Medical University, Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing, China; Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing, China
| | - Xunming Ji
- Beijing Key Laboratory of Hypoxia Translational Medicine, Xuanwu Hospital, Capital Medical University, Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing, China; Center of Stroke, Beijing Institute of Brain Disorder, Capital Medical University, Beijing, China.
| | - Kunlin Jin
- Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
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33
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Fame RM, Lehtinen MK. Mitochondria in Early Forebrain Development: From Neurulation to Mid-Corticogenesis. Front Cell Dev Biol 2021; 9:780207. [PMID: 34888312 PMCID: PMC8650308 DOI: 10.3389/fcell.2021.780207] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 11/10/2021] [Indexed: 01/07/2023] Open
Abstract
Function of the mature central nervous system (CNS) requires a substantial proportion of the body’s energy consumption. During development, the CNS anlage must maintain its structure and perform stage-specific functions as it proceeds through discrete developmental stages. While key extrinsic signals and internal transcriptional controls over these processes are well appreciated, metabolic and mitochondrial states are also critical to appropriate forebrain development. Specifically, metabolic state, mitochondrial function, and mitochondrial dynamics/localization play critical roles in neurulation and CNS progenitor specification, progenitor proliferation and survival, neurogenesis, neural migration, and neurite outgrowth and synaptogenesis. With the goal of integrating neurodevelopmental biologists and mitochondrial specialists, this review synthesizes data from disparate models and processes to compile and highlight key roles of mitochondria in the early development of the CNS with specific focus on forebrain development and corticogenesis.
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Affiliation(s)
- Ryann M Fame
- Department of Pathology, Boston Children's Hospital, Boston, MA, United States
| | - Maria K Lehtinen
- Department of Pathology, Boston Children's Hospital, Boston, MA, United States
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Yao S, Janku F, Koenig K, Tsimberidou AM, Piha-Paul SA, Shi N, Stewart J, Johnston A, Bomalaski J, Meric-Bernstam F, Fu S. Phase 1 trial of ADI-PEG 20 and liposomal doxorubicin in patients with metastatic solid tumors. Cancer Med 2021; 11:340-347. [PMID: 34841717 PMCID: PMC8729058 DOI: 10.1002/cam4.4446] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 11/07/2021] [Accepted: 11/09/2021] [Indexed: 01/30/2023] Open
Abstract
Background Arginine depletion interferes with pyrimidine metabolism and DNA damage repair pathways. Preclinical data demonstrated that depletion of arginine by PEGylated arginine deiminase (ADI‐PEG 20) enhanced liposomal doxorubicin (PLD) cytotoxicity in cancer cells with argininosuccinate synthase 1 (ASS1) deficiency. The objective of this study was to assess safety and tolerability of ADI‐PEG 20 and PLD in patients with metastatic solid tumors. Methods Patients with advanced ASS1‐deficient solid tumors were enrolled in this phase 1 trial of ADI‐PEG 20 and PLD following a 3 + 3 design. Eligible patients were given intravenous PLD biweekly and intramuscular (IM) ADI‐PEG 20 weekly. Toxicity and efficacy were evaluated according to the Common Terminology Criteria for Adverse Events (version 4.0) and Response Evaluation Criteria in Solid Tumors (version 1.1), respectively. Results Of 15 enrolled patients, 9 had metastatic HER2‐negative breast carcinoma. We observed no dose‐limiting toxicities or treatment‐related deaths. One patient safely received 880 mg/m2 PLD in this study and 240 mg/m2 doxorubicin previously. Treatment led to stable disease in 9 patients and was associated with a median progression‐free survival time of 3.95 months in 15 patients. Throughout the duration of treatment, decreased arginine and increased citrulline levels in peripheral blood remained significant in a majority of patients. We detected no induction of anti‐ADI‐PEG 20 antibodies by week 8 in one third of patients. Conclusion Concurrent IM injection of ADI‐PEG 20 at 36 mg/m2 weekly and intravenous infusion of PLD at 20 mg/m2 biweekly had an acceptable safety profile in patients with advanced ASS1‐deficient solid tumors. Further evaluation of this combination is under discussion.
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Affiliation(s)
- Shuyang Yao
- Department of Investigational Cancer Therapeutics, Houston, Texas, USA.,Department of Thoracic Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Filip Janku
- Department of Investigational Cancer Therapeutics, Houston, Texas, USA
| | | | | | | | - Nai Shi
- Department of Investigational Cancer Therapeutics, Houston, Texas, USA
| | - John Stewart
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | | - John Bomalaski
- Polaris Pharmaceuticals, Inc., San Diego, California, USA
| | | | - Siqing Fu
- Department of Investigational Cancer Therapeutics, Houston, Texas, USA
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35
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Landry T, Huang H. Mini review: The relationship between energy status and adult hippocampal neurogenesis. Neurosci Lett 2021; 765:136261. [PMID: 34562518 DOI: 10.1016/j.neulet.2021.136261] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 08/09/2021] [Accepted: 09/17/2021] [Indexed: 01/10/2023]
Abstract
The ability to generate new hippocampal neurons throughout adulthood and successfully integrate them into existing neural networks is critical to cognitive function, while disordered regulation of this process results in neurodegenerative or psychiatric disease. Consequently, identifying the molecular mechanisms promoting homeostatic hippocampal neurogenesis in adults is essential to understanding the etiologies of these disorders and developing therapeutic interventions. For example, recent evidence identifies a strong association between metabolic function and adult hippocampal neurogenesis. Hippocampal neural stem cell (NSC) fate dynamically fluctuates with changes in substrate availability and energy status (AMP/ATP and NAD+/NADH ratios). Furthermore, many metabolic hormones, such as insulin, insulin-like growth factors, and leptin exhibit dual functions also modulating hippocampal neurogenesis and neuron survivability. These diverse metabolic inputs to NSC's from various tissues seemingly suggest the existence of a system in which energy status can finely modulate hippocampal neurogenesis. Supporting this hypothesis, interventions promoting energy balance, such as caloric restriction, intermittent fasting, and exercise, have shown encouraging potential enhancing hippocampal neurogenesis and cognitive function. Overall, there is a clear relationship between whole body energy status, adult hippocampal neurogenesis, and neuron survival; however, the molecular mechanisms underlying this phenomenon are multifaceted. Thus, the aim of this review is to analyze the literature investigating energy status-mediated regulation of adult neurogenesis in the hippocampus, highlight the neurocircuitry and intracellular signaling involved, and propose impactful future directions in the field.
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Affiliation(s)
- Taylor Landry
- East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA; Department of Kinesiology, East Carolina University, Greenville, NC, USA; Human Performance Laboratory, College of Human Performance and Health, East Carolina University, Greenville, NC, USA.
| | - Hu Huang
- East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC, USA; Department of Kinesiology, East Carolina University, Greenville, NC, USA; Human Performance Laboratory, College of Human Performance and Health, East Carolina University, Greenville, NC, USA; Department of Physiology, East Carolina University, Greenville, NC, USA.
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Mahony C, O’Ryan C. Convergent Canonical Pathways in Autism Spectrum Disorder from Proteomic, Transcriptomic and DNA Methylation Data. Int J Mol Sci 2021; 22:ijms221910757. [PMID: 34639097 PMCID: PMC8509728 DOI: 10.3390/ijms221910757] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/27/2021] [Accepted: 10/01/2021] [Indexed: 12/20/2022] Open
Abstract
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with extensive genetic and aetiological heterogeneity. While the underlying molecular mechanisms involved remain unclear, significant progress has been facilitated by recent advances in high-throughput transcriptomic, epigenomic and proteomic technologies. Here, we review recently published ASD proteomic data and compare proteomic functional enrichment signatures with those of transcriptomic and epigenomic data. We identify canonical pathways that are consistently implicated in ASD molecular data and find an enrichment of pathways involved in mitochondrial metabolism and neurogenesis. We identify a subset of differentially expressed proteins that are supported by ASD transcriptomic and DNA methylation data. Furthermore, these differentially expressed proteins are enriched for disease phenotype pathways associated with ASD aetiology. These proteins converge on protein–protein interaction networks that regulate cell proliferation and differentiation, metabolism, and inflammation, which demonstrates a link between canonical pathways, biological processes and the ASD phenotype. This review highlights how proteomics can uncover potential molecular mechanisms to explain a link between mitochondrial dysfunction and neurodevelopmental pathology.
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Early Life Stress and Metabolic Plasticity of Brain Cells: Impact on Neurogenesis and Angiogenesis. Biomedicines 2021; 9:biomedicines9091092. [PMID: 34572278 PMCID: PMC8470044 DOI: 10.3390/biomedicines9091092] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/15/2021] [Accepted: 08/23/2021] [Indexed: 12/15/2022] Open
Abstract
Early life stress (ELS) causes long-lasting changes in brain plasticity induced by the exposure to stress factors acting prenatally or in the early postnatal ontogenesis due to hyperactivation of hypothalamic-pituitary-adrenal axis and sympathetic nervous system, development of neuroinflammation, aberrant neurogenesis and angiogenesis, and significant alterations in brain metabolism that lead to neurological deficits and higher susceptibility to development of brain disorders later in the life. As a key component of complex pathogenesis, ELS-mediated changes in brain metabolism associate with development of mitochondrial dysfunction, loss of appropriate mitochondria quality control and mitochondrial dynamics, deregulation of metabolic reprogramming. These mechanisms are particularly critical for maintaining the pool and development of brain cells within neurogenic and angiogenic niches. In this review, we focus on brain mitochondria and energy metabolism related to tightly coupled neurogenic and angiogenic events in healthy and ELS-affected brain, and new opportunities to develop efficient therapeutic strategies aimed to restore brain metabolism and reduce ELS-induced impairments of brain plasticity.
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Iwata R, Vanderhaeghen P. Regulatory roles of mitochondria and metabolism in neurogenesis. Curr Opin Neurobiol 2021; 69:231-240. [PMID: 34171617 PMCID: PMC8415079 DOI: 10.1016/j.conb.2021.05.003] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/14/2021] [Accepted: 05/18/2021] [Indexed: 01/14/2023]
Abstract
Neural stem cells (NSCs) undergo massive molecular and cellular changes during neuronal differentiation. These include mitochondria and metabolism remodelling, which were thought to be mostly permissive cues, but recent work indicates that they are causally linked to neurogenesis. Striking remodelling of mitochondria occurs right after mitosis of NSCs, which influences the postmitotic daughter cells towards self-renewal or differentiation. The transitioning to neuronal fate requires metabolic rewiring including increased oxidative phosphorylation activity, which drives transcriptional and epigenetic effects to influence cell fate. Mitochondria metabolic pathways also contribute in an essential way to the regulation of NSC proliferation and self-renewal. The influence of mitochondria and metabolism on neurogenesis is conserved from fly to human systems, but also displays striking differences linked to cell context or species. These new findings have important implications for our understanding of neurodevelopmental diseases and possibly human brain evolution.
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Affiliation(s)
- Ryohei Iwata
- VIB KULeuven Center for Brain & Disease Research, KU Leuven Department of Neurosciences, Leuven Brain Institute, Leuven, 3000, Belgium; Université Libre de Bruxelles (ULB), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), ULB Neuroscience Institute (UNI), Brussels, 1070, Belgium
| | - Pierre Vanderhaeghen
- VIB KULeuven Center for Brain & Disease Research, KU Leuven Department of Neurosciences, Leuven Brain Institute, Leuven, 3000, Belgium; Université Libre de Bruxelles (ULB), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), ULB Neuroscience Institute (UNI), Brussels, 1070, Belgium.
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Traxler L, Lagerwall J, Eichhorner S, Stefanoni D, D'Alessandro A, Mertens J. Metabolism navigates neural cell fate in development, aging and neurodegeneration. Dis Model Mech 2021; 14:dmm048993. [PMID: 34345916 PMCID: PMC8353098 DOI: 10.1242/dmm.048993] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
An uninterrupted energy supply is critical for the optimal functioning of all our organs, and in this regard the human brain is particularly energy dependent. The study of energy metabolic pathways is a major focus within neuroscience research, which is supported by genetic defects in the oxidative phosphorylation mechanism often contributing towards neurodevelopmental disorders and changes in glucose metabolism presenting as a hallmark feature in age-dependent neurodegenerative disorders. However, as recent studies have illuminated roles of cellular metabolism that span far beyond mere energetics, it would be valuable to first comprehend the physiological involvement of metabolic pathways in neural cell fate and function, and to subsequently reconstruct their impact on diseases of the brain. In this Review, we first discuss recent evidence that implies metabolism as a master regulator of cell identity during neural development. Additionally, we examine the cell type-dependent metabolic states present in the adult brain. As metabolic states have been studied extensively as crucial regulators of malignant transformation in cancer, we reveal how knowledge gained from the field of cancer has aided our understanding in how metabolism likewise controls neural fate determination and stability by directly wiring into the cellular epigenetic landscape. We further summarize research pertaining to the interplay between metabolic alterations and neurodevelopmental and psychiatric disorders, and expose how an improved understanding of metabolic cell fate control might assist in the development of new concepts to combat age-dependent neurodegenerative diseases, particularly Alzheimer's disease.
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Affiliation(s)
- Larissa Traxler
- Neural Aging Laboratory, Institute of Molecular Biology, CMBI, Leopold-Franzens-University Innsbruck, Tyrol 6020, Austria
| | - Jessica Lagerwall
- Neural Aging Laboratory, Institute of Molecular Biology, CMBI, Leopold-Franzens-University Innsbruck, Tyrol 6020, Austria
| | - Sophie Eichhorner
- Neural Aging Laboratory, Institute of Molecular Biology, CMBI, Leopold-Franzens-University Innsbruck, Tyrol 6020, Austria
| | - Davide Stefanoni
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045, USA
| | - Angelo D'Alessandro
- Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Aurora, CO 80045, USA
| | - Jerome Mertens
- Neural Aging Laboratory, Institute of Molecular Biology, CMBI, Leopold-Franzens-University Innsbruck, Tyrol 6020, Austria
- Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
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White CJ, Ellis JM, Wolfgang MJ. The role of ethanolamine phosphate phospholyase in regulation of astrocyte lipid homeostasis. J Biol Chem 2021; 297:100830. [PMID: 34048714 PMCID: PMC8233209 DOI: 10.1016/j.jbc.2021.100830] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/14/2021] [Accepted: 05/24/2021] [Indexed: 11/18/2022] Open
Abstract
Dietary lipid composition has been shown to impact brain morphology, brain development, and neurologic function. However, how diet uniquely regulates brain lipid homeostasis compared with lipid homeostasis in peripheral tissues remains largely uncharacterized. To evaluate the lipid response to dietary changes in the brain, we assessed actively translating mRNAs in astrocytes and neurons across multiple diets. From this data, ethanolamine phosphate phospholyase (Etnppl) was identified as an astrocyte-specific fasting-induced gene. Etnppl catabolizes phosphoethanolamine (PEtN), a prominent headgroup precursor in phosphatidylethanolamine (PE) also found in other classes of neurologically relevant lipid species. Altered Etnppl expression has also previously been associated with humans with mood disorders. We evaluated the relevance of Etnppl in maintaining brain lipid homeostasis by characterizing Etnppl across development and in coregulation with PEtN-relevant genes, as well as determining the impact to the brain lipidome after Etnppl loss. We found that Etnppl expression dramatically increased during a critical window of early brain development in mice and was also induced by glucocorticoids. Using a constitutive knockout of Etnppl (EtnpplKO), we did not observe robust changes in expression of PEtN-related genes. However, loss of Etnppl altered the phospholipid profile in the brain, resulting in increased total abundance of PE and in polyunsaturated fatty acids within PE and phosphatidylcholine species in the brain. Together, these data suggest that brain phospholipids are regulated by the phospholyase action of the enzyme Etnppl, which is induced by dietary fasting in astrocytes.
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Affiliation(s)
- Cory J White
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jessica M Ellis
- Department of Physiology, East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, North Carolina, USA
| | - Michael J Wolfgang
- Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
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Dodson M, Anandhan A, Zhang DD, Madhavan L. An NRF2 Perspective on Stem Cells and Ageing. FRONTIERS IN AGING 2021; 2:690686. [PMID: 36213179 PMCID: PMC9536878 DOI: 10.3389/fragi.2021.690686] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 06/03/2021] [Indexed: 04/24/2023]
Abstract
Redox and metabolic mechanisms lie at the heart of stem cell survival and regenerative activity. NRF2 is a major transcriptional controller of cellular redox and metabolic homeostasis, which has also been implicated in ageing and lifespan regulation. However, NRF2's role in stem cells and their functioning with age is only just emerging. Here, focusing mainly on neural stem cells, which are core to adult brain plasticity and function, we review recent findings that identify NRF2 as a fundamental player in stem cell biology and ageing. We also discuss NRF2-based molecular programs that may govern stem cell state and function with age, and implications of this for age-related pathologies.
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Affiliation(s)
- Matthew Dodson
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, United States
| | - Annadurai Anandhan
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, United States
- Department of Neurology, University of Arizona, Tucson, AZ, United States
| | - Donna D. Zhang
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, United States
| | - Lalitha Madhavan
- Department of Neurology, University of Arizona, Tucson, AZ, United States
- Evelyn F. McKnight Brain Institute and Bio5 Institute, University of Arizona, Tucson, AZ, United States
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Phase 1 trial of ADI-PEG20 plus cisplatin in patients with pretreated metastatic melanoma or other advanced solid malignancies. Br J Cancer 2021; 124:1533-1539. [PMID: 33674736 DOI: 10.1038/s41416-020-01230-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 12/02/2020] [Accepted: 12/10/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Arginine depletion interferes with pyrimidine metabolism and DNA damage-repair pathways, and pairing arginine deiminase pegylated with 20,000-molecular-weight polyethylene glycol (ADI-PEG20) with platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs. METHODS This single-centre, Phase 1 trial was conducted using a 3 + 3 dose escalation designed to assess safety, tolerability and determine the recommended Phase 2 dose (RP2D) of ADI-PEG20. RESULTS We enrolled 99 patients with metastatic argininosuccinate synthetase 1 (ASS1) deficient malignancies. We observed no dose-limiting toxic effects or treatment-related mortality. Three percent of patients discontinued treatment because of toxicity. After treatment, 5% (5/99) of patients had partial responses, and 41% had stable disease. The median progression-free and overall survival durations were 3.62 and 8.06 months, respectively. Substantial arginine depletion and citrulline escalation persisted in most patients through weeks 24 and 8, respectively. Tumour responses were associated with anti-ADI-PEG20 antibody levels at weeks 8 and 16 (p = 0.031 and p = 0.0357, respectively). CONCLUSION Concurrently administered ADI-PEG20 and cisplatin had an acceptable safety profile and had shown antitumour activity against metastatic ASS1-deficient solid tumours. Further evaluation of this treatment combination is warranted.
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Tran SMS, Mohajeri MH. The Role of Gut Bacterial Metabolites in Brain Development, Aging and Disease. Nutrients 2021; 13:732. [PMID: 33669008 PMCID: PMC7996516 DOI: 10.3390/nu13030732] [Citation(s) in RCA: 123] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 02/15/2021] [Accepted: 02/22/2021] [Indexed: 02/07/2023] Open
Abstract
In the last decade, emerging evidence has reported correlations between the gut microbiome and human health and disease, including those affecting the brain. We performed a systematic assessment of the available literature focusing on gut bacterial metabolites and their associations with diseases of the central nervous system (CNS). The bacterial metabolites short-chain fatty acids (SCFAs) as well as non-SCFAs like amino acid metabolites (AAMs) and bacterial amyloids are described in particular. We found significantly altered SCFA levels in patients with autism spectrum disorder (ASD), affective disorders, multiple sclerosis (MS) and Parkinson's disease (PD). Non-SCFAs yielded less significantly distinct changes in faecal levels of patients and healthy controls, with the majority of findings were derived from urinary and blood samples. Preclinical studies have implicated different bacterial metabolites with potentially beneficial as well as detrimental mechanisms in brain diseases. Examples include immunomodulation and changes in catecholamine production by histone deacetylase inhibition, anti-inflammatory effects through activity on the aryl hydrocarbon receptor and involvement in protein misfolding. Overall, our findings highlight the existence of altered bacterial metabolites in patients across various brain diseases, as well as potential neuroactive effects by which gut-derived SCFAs, p-cresol, indole derivatives and bacterial amyloids could impact disease development and progression. The findings summarized in this review could lead to further insights into the gut-brain-axis and thus into potential diagnostic, therapeutic or preventive strategies in brain diseases.
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Affiliation(s)
| | - M. Hasan Mohajeri
- Department of Medicine, Institute of Anatomy, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland;
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Abstract
Traumatic brain injury (TBI) is a major cause of mortality and morbidity in the pediatric population. With advances in medical care, the mortality rate of pediatric TBI has declined. However, more children and adolescents are living with TBI-related cognitive and emotional impairments, which negatively affects the quality of their life. Adult hippocampal neurogenesis plays an important role in cognition and mood regulation. Alterations in adult hippocampal neurogenesis are associated with a variety of neurological and neurodegenerative diseases, including TBI. Promoting endogenous hippocampal neurogenesis after TBI merits significant attention. However, TBI affects the function of neural stem/progenitor cells in the dentate gyrus of hippocampus, which results in aberrant migration and impaired dendrite development of adult-born neurons. Therefore, a better understanding of adult hippocampal neurogenesis after TBI can facilitate a more successful neuro-restoration of damage in immature brains. Secondary injuries, such as neuroinflammation and oxidative stress, exert a significant impact on hippocampal neurogenesis. Currently, a variety of therapeutic approaches have been proposed for ameliorating secondary TBI injuries. In this review, we discuss the uniqueness of pediatric TBI, adult hippocampal neurogenesis after pediatric TBI, and current efforts that promote neuroprotection to the developing brains, which can be leveraged to facilitate neuroregeneration.
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Affiliation(s)
- Mariam Rizk
- Department of Natural Sciences, University of Michigan-Dearborn, Dearborn, MI, USA
| | - Justin Vu
- Department of Natural Sciences, University of Michigan-Dearborn, Dearborn, MI, USA
| | - Zhi Zhang
- Department of Natural Sciences, University of Michigan-Dearborn, Dearborn, MI, USA
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Hoang G, Nguyen K, Le A. Metabolic Intersection of Cancer and Cardiovascular Diseases: Opportunities for Cancer Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1311:249-263. [PMID: 34014548 PMCID: PMC9703259 DOI: 10.1007/978-3-030-65768-0_18] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
According to data from the World Health Organization, cardiovascular diseases and cancer are the two leading causes of mortality in the world [1]. Despite the immense effort to study these diseases and the constant innovation in treatment modalities, the number of deaths associated with cardiovascular diseases and cancer is predicted to increase in the coming decades [1]. From 2008 to 2030, due to population growth and population aging in many parts of the world, the number of deaths caused by cancer globally is projected to increase by 45%, corresponding to an annual increase of around four million people [1]. For cardiovascular diseases, this number is six million people [1]. In the United States, treatments for these two diseases are among the most costly and result in a disproportionate impact on low- and middleincome people. As the fight against these fatal diseases continues, it is crucial that we continue our investigation and broaden our understanding of cancer and cardiovascular diseases to innovate our prognostic and treatment approaches. Even though cardiovascular diseases and cancer are usually studied independently [2-12], there are some striking overlaps between their metabolic behaviors and therapeutic targets, suggesting the potential application of cardiovascular disease treatments for cancer therapy. More specifically, both cancer and many cardiovascular diseases have an upregulated glutaminolysis pathway, resulting in low glutamine and high glutamate circulating levels. Similar treatment modalities, such as glutaminase (GLS) inhibition and glutamine supplementation, have been identified to target glutamine metabolism in both cancer and some cardiovascular diseases. Studies have also found similarities in lipid metabolism, specifically fatty acid oxidation (FAO) and synthesis. Pharmacological inhibition of FAO and fatty acid synthesis have proven effective against many cancer types as well as specific cardiovascular conditions. Many of these treatments have been tested in clinical trials, and some have been medically prescribed to patients to treat certain diseases, such as angina pectoris [13, 14]. Other metabolic pathways, such as tryptophan catabolism and pyruvate metabolism, were also dysregulated in both diseases, making them promising treatment targets. Understanding the overlapping traits exhibited by both cancer metabolism and cardiovascular disease metabolism can give us a more holistic view of how important metabolic dysregulation is in the progression of diseases. Using established links between these illnesses, researchers can take advantage of the discoveries from one field and potentially apply them to the other. In this chapter, we highlight some promising therapeutic discoveries that can support our fight against cancer, based on common metabolic traits displayed in both cancer and cardiovascular diseases.
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Affiliation(s)
- Giang Hoang
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD, USA
| | - Kiet Nguyen
- Department of Chemistry and Biology, Emory University, Atlanta, GA, USA
| | - Anne Le
- Department of Pathology and Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University Whiting School of Engineering, Baltimore, MD, USA.
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Abnormalities of synaptic mitochondria in autism spectrum disorder and related neurodevelopmental disorders. J Mol Med (Berl) 2020; 99:161-178. [PMID: 33340060 PMCID: PMC7819932 DOI: 10.1007/s00109-020-02018-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 11/27/2020] [Accepted: 12/02/2020] [Indexed: 12/18/2022]
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental condition primarily characterized by an impairment of social interaction combined with the occurrence of repetitive behaviors. ASD starts in childhood and prevails across the lifespan. The variability of its clinical presentation renders early diagnosis difficult. Mutations in synaptic genes and alterations of mitochondrial functions are considered important underlying pathogenic factors, but it is obvious that we are far from a comprehensive understanding of ASD pathophysiology. At the synapse, mitochondria perform diverse functions, which are clearly not limited to their classical role as energy providers. Here, we review the current knowledge about mitochondria at the synapse and summarize the mitochondrial disturbances found in mouse models of ASD and other ASD-related neurodevelopmental disorders, like DiGeorge syndrome, Rett syndrome, Tuberous sclerosis complex, and Down syndrome.
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Namba T, Nardelli J, Gressens P, Huttner WB. Metabolic Regulation of Neocortical Expansion in Development and Evolution. Neuron 2020; 109:408-419. [PMID: 33306962 DOI: 10.1016/j.neuron.2020.11.014] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/19/2020] [Accepted: 11/13/2020] [Indexed: 12/18/2022]
Abstract
The neocortex, the seat of our higher cognitive abilities, has expanded in size during the evolution of certain mammals such as primates, including humans. This expansion occurs during development and is linked to the proliferative capacity of neural stem and progenitor cells (NPCs) in the neocortex. A number of cell-intrinsic and cell-extrinsic factors have been implicated in increasing NPC proliferative capacity. However, NPC metabolism has only recently emerged as major regulator of NPC proliferation. In this Perspective, we summarize recent insights into the role of NPC metabolism in neocortical development and neurodevelopmental disorders and its relevance for neocortex evolution. We discuss certain human-specific genes and microcephaly-implicated genes that operate in, or at, the mitochondria of NPCs and stimulate their proliferation by promoting glutaminolysis. We also discuss other metabolic pathways and develop a perspective on how metabolism mechanistically regulates NPC proliferation in neocortical development and how this contributed to neocortex evolution.
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Affiliation(s)
- Takashi Namba
- Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany; Neuroscience Center, HiLIFE - Helsinki Institute of Life Science, University of Helsinki, 00014 Helsinki, Finland
| | | | - Pierre Gressens
- Université de Paris, NeuroDiderot, Inserm, 75019 Paris, France.
| | - Wieland B Huttner
- Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany.
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Fadó R, Rodríguez-Rodríguez R, Casals N. The return of malonyl-CoA to the brain: Cognition and other stories. Prog Lipid Res 2020; 81:101071. [PMID: 33186641 DOI: 10.1016/j.plipres.2020.101071] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/06/2020] [Accepted: 11/08/2020] [Indexed: 12/11/2022]
Abstract
Nutrients, hormones and the energy sensor AMP-activated protein kinase (AMPK) tightly regulate the intracellular levels of the metabolic intermediary malonyl-CoA, which is a precursor of fatty acid synthesis and a negative regulator of fatty acid oxidation. In the brain, the involvement of malonyl-CoA in the control of food intake and energy homeostasis has been known for decades. However, recent data uncover a new role in cognition and brain development. The sensing of malonyl-CoA by carnitine palmitoyltransferase 1 (CPT1) proteins regulates a variety of functions, such as the fate of neuronal stem cell precursors, the motility of lysosomes in developing axons, the trafficking of glutamate receptors to the neuron surface (necessary for proper synaptic function) and the metabolic coupling between astrocytes and neurons. We discuss the relevance of those recent findings evidencing how nutrients and metabolic disorders impact cognition. We also enumerate all nutritional and hormonal conditions that are known to regulate malonyl-CoA levels in the brain, reflect on protein malonylation as a new post-translational modification, and give a reasoned vision of the opportunities and challenges that future research in the field could address.
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Affiliation(s)
- Rut Fadó
- Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, E-08195 Sant Cugat del Vallès, Spain; Institut de Neurociències, Universitat Autònoma de Barcelona, 08193, Bellaterra, Cerdanyola del Vallès, Spain.
| | - Rosalía Rodríguez-Rodríguez
- Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, E-08195 Sant Cugat del Vallès, Spain.
| | - Núria Casals
- Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, E-08195 Sant Cugat del Vallès, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, E-28029 Madrid, Spain.
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49
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Langlois PH, Canfield MA, Rutenberg GW, Mandell DJ, Hua F, Reilly B, Ruktanonchai DJ, Jackson JF, Hunt P, Freedenberg D, Lee R, Villanacci JF. The association between newborn screening analytes as measured on a second screen and childhood autism in a Texas Medicaid population. Am J Med Genet B Neuropsychiatr Genet 2020; 183:331-340. [PMID: 32657040 DOI: 10.1002/ajmg.b.32804] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/31/2020] [Accepted: 04/08/2020] [Indexed: 12/12/2022]
Abstract
Autism (or autism spectrum disorder [ASD]) is an often disabling childhood neurologic condition of mostly unknown cause. We previously explored whether there was an association of ASD with any analyte measured in the first newborn screening blood test. Here we explore the second screen. Our matched case-control study examined data on 3-5 year-old patients with any ASD diagnosis in the Texas Medicaid system in 2010-2012. Subjects were linked to their 2007-2009 newborn screening blood test data, which included values for 36 analytes or analyte ratios. Data were available for 3,005 cases and 6,212 controls. The most compelling associations were evident for fatty acid oxidation analytes octanoylcarnitine (C8) and octanoylcarnitine/acetylcarnitine (C8/C2). Their adjusted odds ratios comparing 10th versus first analyte deciles were between 1.42 and 1.54 in total births, term births, and males. C8 was consistent with first screen results. Adipylcarnitine (C6DC), an organic acid analyte, showed opposite results in the two screens. Several other analytes exhibiting significant associations in the first screen did not in the second. Our results provide evidence that abnormal newborn blood levels of some carnitines may be associated with risk of later ASD, possibly related to their involvement with mitochondrial function in the developing brain.
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Affiliation(s)
- Peter H Langlois
- Birth Defects Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, Texas, USA
| | - Mark A Canfield
- Birth Defects Epidemiology and Surveillance Branch, Texas Department of State Health Services, Austin, Texas, USA
| | - Gary W Rutenberg
- Center for Analytics and Decision Support, Texas Health and Human Services Commission, Austin, Texas, USA
| | - Dorothy J Mandell
- School of Community and Rural Health, University of Texas Health Science Center, Tyler, Texas, USA.,Population Health, Office of Health Affairs, UT System, Austin, Texas, USA
| | - Fei Hua
- Center for Health Statistics, Texas Department of State Health Services, Austin, Texas, USA
| | - Brendan Reilly
- Biochemistry and Genetics Branch, Laboratory Services Section, Texas Department of State Health Services, Austin, Texas, USA
| | - Duke J Ruktanonchai
- Children's Institute of Pittsburgh, Pittsburgh, Pennsylvania, USA.,Wesley Family Services, Pittsburgh, Pennsylvania, USA
| | - Janice F Jackson
- Center for Analytics and Decision Support, Texas Health and Human Services Commission, Austin, Texas, USA
| | - Patricia Hunt
- Biochemistry and Genetics Branch, Laboratory Services Section, Texas Department of State Health Services, Austin, Texas, USA
| | - Debra Freedenberg
- Newborn Screening and Genetics Unit, Texas Department of State Health Services, Austin, Texas, USA
| | - Rachel Lee
- Biochemistry and Genetics Branch, Laboratory Services Section, Texas Department of State Health Services, Austin, Texas, USA
| | - John F Villanacci
- Environmental Epidemiology and Disease Registries Section, Texas Department of State Health Services, Austin, Texas, USA
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50
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Sênos Demarco R, Clémot M, Jones DL. The impact of ageing on lipid-mediated regulation of adult stem cell behavior and tissue homeostasis. Mech Ageing Dev 2020; 189:111278. [PMID: 32522455 DOI: 10.1016/j.mad.2020.111278] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 05/05/2020] [Accepted: 06/01/2020] [Indexed: 02/06/2023]
Abstract
Adult stem cells sustain tissue homeostasis throughout life and provide an important reservoir of cells capable of tissue repair in response to stress and tissue damage. Age-related changes to stem cells and/or the specialized niches that house them have been shown to negatively impact stem cell maintenance and activity. In addition, metabolic inputs have surfaced as another crucial layer in the control of stem cell behavior (Chandel et al., 2016; Folmes and Terzic, 2016; Ito and Suda, 2014; Mana et al., 2017; Shyh-Chang and Ng, 2017). Here, we will present a brief review of how lipid metabolism influences adult stem cell behavior under homeostatic conditions and speculate on how changes in lipid metabolism may impact stem cell ageing. This review considers the future of lipid metabolism research in stem cells, with the long-term goal of identifying mechanisms that could be targeted to counter or slow the age-related decline in stem cell function.
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Affiliation(s)
- Rafael Sênos Demarco
- Department of Molecular, Cell and Developmental Biology, Los Angeles, CA, 90095, USA
| | - Marie Clémot
- Department of Molecular, Cell and Developmental Biology, Los Angeles, CA, 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, 90095, USA
| | - D Leanne Jones
- Department of Molecular, Cell and Developmental Biology, Los Angeles, CA, 90095, USA; Molecular Biology Institute, Los Angeles, CA, 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
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