Frequent Truncating Mutation of TFAM Induces Mitochondrial DNA Depletion and Apoptotic Resistance in Microsatellite-Unstable Colorectal Cancer
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Mitochondrial Transcription Factor a Promotes DNA Strand Cleavage at Abasic Sites
Mitochondrial transcription factor A promotes DNA strand cleavage at abasic sites Wenyan Xu (许文彦)a,1, Riley M. Boyda,1, Maya O. Treea, Faris Samkaria, and Linlin Zhaoa,b,2,3 aDepartment of Chemistry and Biochemistry, Central Michigan University, Mount Pleasant, MI 48859; and bBiochemistry, Cellular, and Molecular Biology Graduate Program, Central Michigan University, Mount Pleasant, MI 48859 Edited by Rafael Radi, Universidad de la Republica, Montevideo, Uruguay, and approved July 18, 2019 (received for review July 2, 2019) In higher eukaryotic cells, mitochondria are essential subcellular damage in cells (13, 14). Within mitochondria, AP lesions are organelles for energy production, cell signaling, and the biosynthesis also abundant and can number in the hundreds per cell, con- of biomolecules. The mitochondrial DNA (mtDNA) genome is in- sidering their steady-state level (0.2 to 3 AP sites per 105 bp) (15, dispensable for mitochondrial function because it encodes protein 16) and the number of mtDNA copies per cell (∼1,000) (17). subunits of the electron transport chain and a full set of transfer and Importantly, AP sites are chemically labile and reactive and can ribosomal RNAs. MtDNA degradation has emerged as an essential lead to secondary DNA damage such as DNA single-strand quality control measure to maintain mtDNA and to cope with mtDNA breaks (SSBs), DNA–DNA interstrand cross-links, and DNA– damage resulting from endogenous and environmental factors. protein cross-links (DPCs) (18–23). If not repaired, AP sites Among all types of DNA damage known, abasic (AP) sites, sourced and their derivatives are mutagenic in the nuclear genome (24– from base excision repair and spontaneous base loss, are the most 26); however, the understanding of the biological consequence of abundant endogenous DNA lesions in cells. -
Transcription from the Second Heavy-Strand Promoter of Human Mtdna Is Repressed by Transcription Factor a in Vitro
Transcription from the second heavy-strand promoter of human mtDNA is repressed by transcription factor A in vitro Maria F. Lodeiroa, Akira Uchidaa, Megan Bestwickb, Ibrahim M. Moustafaa, Jamie J. Arnolda, Gerald S. Shadelb,c, and Craig E. Camerona,1 aDepartment of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802; bDepartment of Pathology, Yale University School of Medicine, New Haven, CT 06520; and cDepartment of Genetics, Yale University School of Medicine, New Haven, CT 06520 Edited* by Douglas C. Wallace, Center for Mitochondrial and Epigenomic Medicine (CMEM), Children’s Hospital of Philadelphia, Philadelphia, PA, and approved March 8, 2012 (received for review November 15, 2011) Cell-based studies support the existence of two promoters on the factor B2 (TFB2M). The long-standing paradigm was that TFAM heavy strand of mtDNA: heavy-strand promoter 1 (HSP1) and HSP2. binds to a site in the promoter upstream of the transcription start However, transcription from HSP2 has been reported only once in site and recruits a complex POLRMT/TFB2M by an interaction of a cell-free system, and never when recombinant proteins have been the carboxyl-terminal tail of TFAM with TFB2M (3). However, we used. Here, we document transcription from HSP2 using an in vitro recently showed that basal mitochondrial transcription is not ab- system of defined composition. An oligonucleotide template repre- solutely dependent on TFAM (4). This observation suggested that senting positions 596–685 of mtDNA was sufficient to observe tran- the two-component transcription system found in lower eukaryotes scription by the human mtRNA polymerase (POLRMT) that was had acquired an additional layer of regulation in mammals that is absolutely dependent on mitochondrial transcription factor B2 mediated by TFAM (4). -
Mitochondrial Dysfunction in Sepsis Is Associated with Diminished
www.nature.com/scientificreports OPEN Mitochondrial dysfunction in sepsis is associated with diminished intramitochondrial TFAM despite its increased cellular expression Tim Rahmel 1*, Britta Marko1, Hartmuth Nowak1, Lars Bergmann1, Patrick Thon1, Katharina Rump1, Sebastian Kreimendahl2, Joachim Rassow2, Jürgen Peters3, Mervyn Singer4, Michael Adamzik1,5 & Björn Koos1,5 Sepsis is characterized by a dysregulated immune response, metabolic derangements and bioenergetic failure. These alterations are closely associated with a profound and persisting mitochondrial dysfunction. This however occurs despite increased expression of the nuclear-encoded transcription factor A (TFAM) that normally supports mitochondrial biogenesis and functional recovery. Since this paradox may relate to an altered intracellular distribution of TFAM in sepsis, we tested the hypothesis that enhanced extramitochondrial TFAM expression does not translate into increased intramitochondrial TFAM abundance. Accordingly, we prospectively analyzed PBMCs both from septic patients (n = 10) and lipopolysaccharide stimulated PBMCs from healthy volunteers (n = 20). Extramitochondrial TFAM protein expression in sepsis patients was 1.8-fold greater compared to controls (p = 0.001), whereas intramitochondrial TFAM abundance was approximate 80% less (p < 0.001). This was accompanied by lower mitochondrial DNA copy numbers (p < 0.001), mtND1 expression (p < 0.001) and cellular ATP content (p < 0.001) in sepsis patients. These fndings were mirrored in lipopolysaccharide stimulated PBMCs taken from healthy volunteers. Furthermore, TFAM- TFB2M protein interaction within the human mitochondrial core transcription initiation complex, was 74% lower in septic patients (p < 0.001). In conclusion, our fndings, which demonstrate a diminished mitochondrial TFAM abundance in sepsis and endotoxemia, may help to explain the paradox of lacking bioenergetic recovery despite enhanced TFAM expression. -
Mitochondria Turnover and Lysosomal Function in Hematopoietic Stem Cell Metabolism
International Journal of Molecular Sciences Review Mitochondria Turnover and Lysosomal Function in Hematopoietic Stem Cell Metabolism Makiko Mochizuki-Kashio 1, Hiroko Shiozaki 2, Toshio Suda 3,4 and Ayako Nakamura-Ishizu 1,* 1 Microanatomy and Developmental Biology, Tokyo Women’s Medical University, 8-1 Kawadacho, Shinjuku-ku, Tokyo 162-8666, Japan; [email protected] 2 Department of Hematology, Tokyo Women’s Medical University, 8-1 Kawadacho, Shinjuku-ku, Tokyo 162-8666, Japan; [email protected] 3 Cancer Science Institute, National University of Singapore, 14 Medical Drive, MD6, Singapore 117599, Singapore; [email protected] 4 International Research Center for Medical Sciences, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto City 860-0811, Japan * Correspondence: [email protected] Abstract: Hematopoietic stem cells (HSCs) reside in a hypoxic microenvironment that enables glycolysis-fueled metabolism and reduces oxidative stress. Nonetheless, metabolic regulation in organelles such as the mitochondria and lysosomes as well as autophagic processes have been implicated as essential for the determination of HSC cell fate. This review encompasses the current understanding of anaerobic metabolism in HSCs as well as the emerging roles of mitochondrial metabolism and lysosomal regulation for hematopoietic homeostasis. Keywords: hematopoietic stem cells; ROS; mitochondria; lysosome; autophagy; folliculin Citation: Mochizuki-Kashio, M.; Shiozaki, H.; Suda, T.; Nakamura-Ishizu, A. Mitochondria 1. Introduction Turnover and Lysosomal Function in Hematopoietic cells consist of a heterogenous group of cells originating from hematopoi- Hematopoietic Stem Cell Metabolism. etic stem cells (HSCs) [1]. HSCs differentiate into multi-potent progenitor cells (MPPs) Int. J. Mol. Sci. 2021, 22, 4627. -
Cross-Strand Binding of TFAM to a Single Mtdna Molecule Forms the Mitochondrial Nucleoid
Cross-strand binding of TFAM to a single mtDNA molecule forms the mitochondrial nucleoid Christian Kukata,b,1, Karen M. Daviesc,1, Christian A. Wurmd,1, Henrik Spåhra, Nina A. Bonekampa, Inge Kühla, Friederike Joosc, Paola Loguercio Polosae, Chan Bae Parka,f, Viktor Posseg, Maria Falkenbergg, Stefan Jakobsd,h, Werner Kühlbrandtc, and Nils-Göran Larssona,i,2 aDepartment of Mitochondrial Biology, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany; bFACS & Imaging Core Facility, Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany; cDepartment of Structural Biology, Max Planck Institute of Biophysics, 60438 Frankfurt am Main, Germany; dDepartment of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany; eDepartment of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari Aldo Moro, 70125 Bari, Italy; fInstitute for Medical Sciences, Ajou University School of Medicine, Suwon 443-721, Korea; gDepartment of Medical Biochemistry and Cell Biology, University of Gothenburg, 405 30 Gothenburg, Sweden; hDepartment of Neurology, University of Göttingen Medical School, 37073 Göttingen, Germany; and iDepartment of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden Edited by F. Ulrich Hartl, Max Planck Institute of Biochemistry, Martinsried, Germany, and approved August 4, 2015 (received for review June 23, 2015) Mammalian mitochondrial DNA (mtDNA) is packaged by mito- To date, mitochondrial transcription factor A (TFAM) is the chondrial transcription factor A (TFAM) into mitochondrial nucle- only protein that fulfills a stringent definition of a structural oids that are of key importance in controlling the transmission and component that packages mtDNA in the mammalian nucleoid expression of mtDNA. Nucleoid ultrastructure is poorly defined, (8). -
The Tumor Suppressor Folliculin Regulates AMPK-Dependent Metabolic Transformation Ming Yan,1,2 Marie-Claude Gingras,1,2 Elaine A
Downloaded on April 29, 2014. The Journal of Clinical Investigation. More information at www.jci.org/articles/view/71749 Research article The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation Ming Yan,1,2 Marie-Claude Gingras,1,2 Elaine A. Dunlop,3 Yann Nouët,1,2 Fanny Dupuy,1,4 Zahra Jalali,1,2 Elite Possik,1,2 Barry J. Coull,5 Dmitri Kharitidi,1,2 Anders Bondo Dydensborg,1,2 Brandon Faubert,1,4 Miriam Kamps,5 Sylvie Sabourin,1,2 Rachael S. Preston,3 David Mark Davies,3 Taren Roughead,1,2 Laëtitia Chotard,1,2 Maurice A.M. van Steensel,5 Russell Jones,1,4 Andrew R. Tee,3 and Arnim Pause1,2 1Goodman Cancer Research Center and 2Department of Biochemistry, McGill University, Montréal, Québec, Canada. 3Institute of Cancer and Genetics, Cardiff University, Cardiff, Wales, United Kingdom. 4Department of Physiology, McGill University, Montréal, Québec, Canada. 5Department of Dermatology, Maastricht University, Maastricht, The Netherlands. The Warburg effect is a tumorigenic metabolic adaptation process characterized by augmented aerobic gly- colysis, which enhances cellular bioenergetics. In normal cells, energy homeostasis is controlled by AMPK; however, its role in cancer is not understood, as both AMPK-dependent tumor-promoting and -inhibiting functions were reported. Upon stress, energy levels are maintained by increased mitochondrial biogenesis and glycolysis, controlled by transcriptional coactivator PGC-1α and HIF, respectively. In normoxia, AMPK induces PGC-1α, but how HIF is activated is unclear. Germline mutations in the gene encoding the tumor suppressor folliculin (FLCN) lead to Birt-Hogg-Dubé (BHD) syndrome, which is associated with an increased cancer risk. -
Investigation of the Folliculin (Flcn) Tumor Suppressor Gene in Energy Metabolism Ming Yan Department of Biochemistry Mcgill
Investigation of the Folliculin (Flcn) tumor suppressor gene in energy metabolism Ming Yan Department of Biochemistry McGill University Montréal, Canada Dec., 2015 A thesis submitted to McGill University in partial fulfillment of the requirements for the degree of Doctor of Philosophy. © Ming Yan, 2015 ABSTRACT Birt–Hogg–Dubé (BHD) syndrome is an autosomal dominant hereditary disorder characterized by skin fibrofolliculomas, lung cyst, spontaneous pneumothorax and renal cell carcinoma (RCC). This condition is caused by germline mutations of folliculin (Flcn) gene, which encodes a 64-kDa protein named folliculin (FLCN). The AMP-actived protein kinase (AMPK) is a master regulator of cellular energy homeostasis. FLCN interacts with AMPK through FLCN-interacting proteins (FNIP1/2). Molecular function of FLCN and how FLCN interacts with AMPK in energy metabolism are largely unknown. We used mouse embryonic fibroblasts (MEFs) and adipose specific Flcn knockout mouse model to investigate the role of Flcn and its function associated with AMPK in energy metabolism. We found that loss of FLCN constitutively activates AMPK, which in turn leads to elevation in peroxisome proliferator-activated receptor gama coactivator 1 α (PGC-1α), which mediates mitochondrial biogenesis and increase reactive oxygen species (ROS) production. Elevated ROS induces hypoxia-inducible factor (HIF) transcriptional activity and drives Warburg metabolic reprogramming. These findings indicate that Flcn exert tumor suppressor activity by acting as a negative regulator of AMPK-dependent HIF activation and Warburg effect. To investigate the potential role of FLCN/AMPK/ PGC-1α in fat metabolism, we generated an adipose-specific Flcn knockout mouse model. Flcn KO mice exhibit elevated energy expenditure associated with increased O2 consumption, and are protected from diet-induced obesity. -
LONP1 Is Required for Maturation of a Subset of Mitochondrial Proteins and Its Loss Elicits
bioRxiv preprint doi: https://doi.org/10.1101/306316; this version posted April 23, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. LONP1 is required for maturation of a subset of mitochondrial proteins and its loss elicits an integrated stress response Olga Zurita Rendón and Eric A. Shoubridge. Montreal Neurological Institute and Department of Human Genetics, McGill University, Montreal, QC, Canada. Eric A. Shoubridge, Montreal Neurological Institute, 3801 University Street, Montreal, Quebec, Canada H3A 2B4 Email: [email protected] Tel: 514-398-1997 FAX: 514-398-1509 bioRxiv preprint doi: https://doi.org/10.1101/306316; this version posted April 23, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Abstract LONP1, a AAA+ mitochondrial protease, is implicated in protein quality control, but its substrates and precise role in this process remain poorly understood. Here we have investigated the role of human LONP1 in mitochondrial gene expression and proteostasis. Depletion of LONP1 resulted in partial loss of mtDNA, complete suppression of mitochondrial translation, a marked increase in the levels of a distinct subset of mitochondrial matrix proteins (SSBP1, MTERFD3, FASTKD2 and CLPX), and the accumulation of their unprocessed forms, with intact mitochondrial targeting sequences, in an insoluble protein fraction. -
Human Mitochondrial Transcription Factors TFAM and TFB2M Work Synergistically in Promoter Melting During Transcription Initiatio
Published online 28 November 2016 Nucleic Acids Research, 2017, Vol. 45, No. 2 861–874 doi: 10.1093/nar/gkw1157 Human mitochondrial transcription factors TFAM and TFB2M work synergistically in promoter melting during transcription initiation Aparna Ramachandran1, Urmimala Basu1,2, Shemaila Sultana1, Divya Nandakumar1 and Smita S. Patel1,* 1Department of Biochemistry and Molecular Biology, Rutgers, Robert Wood Johnson Medical school, Piscataway, NJ 08854, USA and 2Graduate School of Biomedical Sciences, Rutgers University, Piscataway, NJ 08854, USA Received August 10, 2016; Revised November 02, 2016; Editorial Decision November 04, 2016; Accepted November 04, 2016 ABSTRACT is transcribed by POLRMT, which is homologous to single subunit RNA polymerases from phage T7 and yeast mito- Human mitochondrial DNA is transcribed by POL- chondria (3). T7 RNA polymerase can initiate transcription RMT with the help of two initiation factors, TFAM on its own without any transcription factors (4), the Sac- and TFB2M. The current model postulates that the charomyces cerevisiae Rpo41 requires Mtf1 to initiate tran- role of TFAM is to recruit POLRMT and TFB2M to scription (5–7), and the human POLRMT requires two ini- melt the promoter. However, we show that TFAM tiation factors, TFAM (Transcription Factor A of the Mi- has ‘post-recruitment’ roles in promoter melting and tochondria) and TFB2M (Transcription Factor B2 of the RNA synthesis, which were revealed by studying Mitochondria) for transcript synthesis (8,9). the pre-initiation steps of promoter binding, bend- The initiation factor TFB2M is structurally homologous ing and melting, and abortive RNA synthesis. Our to bacterial RNA methyltransferase ErmC’ (8,10); how- 2-aminopurine mapping studies show that the LSP ever, it has lost most of its RNA methyltransferase activity (11) and serves mainly as the transcription initiation fac- (Light Strand Promoter) is melted from −4to+1in − tor. -
Benzoylaconine Induces Mitochondrial Biogenesis in Mice Via Activating AMPK Signaling Cascade
www.nature.com/aps ARTICLE Benzoylaconine induces mitochondrial biogenesis in mice via activating AMPK signaling cascade Xiao-hong Deng1,2, Jing-jing Liu1,2, Xian-jun Sun1,2, Jing-cheng Dong1,2 and Jian-hua Huang1,2 The traditional Chinese medicine “Fuzi” (Aconiti Lateralis Radix Praeparata) and its three representative alkaloids, aconitine (AC), benzoylaconine (BAC), and aconine, have been shown to increase mitochondrial mass. Whether Fuzi has effect on mitochondrial biogenesis and the underlying mechanisms remain unclear. In the present study, we focused on the effect of BAC on mitochondrial biogenesis and the underlying mechanisms. We demonstrated that Fuzi extract and its three components AC, BAC, and aconine at a concentration of 50 μM significantly increased mitochondrial mass in HepG2 cells. BAC (25, 50, 75 μM) dose-dependently promoted mitochondrial mass, mtDNA copy number, cellular ATP production, and the expression of proteins related to the oxidative phosphorylation (OXPHOS) complexes in HepG2 cells. Moreover, BAC dose-dependently increased the expression of proteins involved in AMPK signaling cascade; blocking AMPK signaling abolished BAC-induced mitochondrial biogenesis. We further revealed that BAC treatment increased the cell viability but not the cell proliferation in HepG2 cells. These in vitro results were verified in mice treated with BAC (10 mg/kg per day, ip) for 7 days. We showed that BAC administration increased oxygen consumption rate in mice, but had no significant effect on intrascapular temperature. Meanwhile, BAC administration increased mtDNA copy number and OXPHOS-related protein expression and activated AMPK signaling in the heart, liver, and muscle. These results suggest that BAC induces mitochondrial biogenesis in mice through activating AMPK signaling cascade. -
Phosphorylation of Human TFAM in Mitochondria Impairs DNA Binding and Promotes Degradation by the AAA+ Lon Protease
Molecular Cell Article Phosphorylation of Human TFAM in Mitochondria Impairs DNA Binding and Promotes Degradation by the AAA+ Lon Protease Bin Lu,1,4,5 Jae Lee,1,5 Xiaobo Nie,1,4,5 Min Li,1 Yaroslav I. Morozov,2 Sundararajan Venkatesh,1 Daniel F. Bogenhagen,3 Dmitry Temiakov,2 and Carolyn K. Suzuki1,* 1Department of Biochemistry and Molecular Biology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA 2Department of Cell Biology, School of Osteopathic Medicine, University of Medicine and Dentistry of New Jersey, Stratford, NJ 08084, USA 3Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794, USA 4Present address: Institute of Biophysics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325035, PRC 5These authors contributed equally to this work *Correspondence: [email protected] http://dx.doi.org/10.1016/j.molcel.2012.10.023 SUMMARY contrast, TFAM overproduction in transgenic mice increases mtDNA content (Ekstrand et al., 2004; Larsson et al., 1998) Human mitochondrial transcription factor A (TFAM) and also ameliorates cardiac failure (Ikeuchi et al., 2005), neuro- is a high-mobility group (HMG) protein at the nexus degeneration, and age-dependent deficits in brain function of mitochondrial DNA (mtDNA) replication, transcrip- (Hokari et al., 2010). TFAM is the most abundant component tion, and inheritance. Little is known about the mech- of mitochondrial nucleoids, which are protein complexes anisms underlying its posttranslational regulation. associated with mtDNA that orchestrate genome replication, Here, we demonstrate that TFAM is phosphorylated expression, and inheritance (Bogenhagen et al., 2008, 2012; Kukat et al., 2011). -
Characterising the Tumour Suppression Function of Folliculin
Characterising the Tumour Suppression Function of Folliculin Rachael Preston 0740708 Thesis submitted for the degree of Doctor of Philosophy 1 Abstract Birt–Hogg–Dubé (BHD) syndrome is a rare inherited autosomal dominant disorder first described by Birt, Hogg and Dube in 1977 (Birt et al,. 1977). BHD affects approximately 100 families worldwide. Approximately one third of diagnosed BHD patients also develop renal cell carcinoma (RCC) (Schmidt et al., 2005). BHD arises as a result of loss of function of the Folliculin protein expressed from the BHD gene, suggesting than Folliculin serves as a tumour suppressor (Vocke et al., 2005). Although it is considered that FLCN represses cell growth, the role that FLCN plays in cancer progression and/or initiation is currently unresolved. It has been observed that tumours taken from BHD patients have reduced levels of mitochondria (Yang et al., 2008). Previous studies have also suggested that aberrant levels of mTOR activity are observed in Folliculin-deficient cell lines (Baba et al., 2006; Baba et al., 2008). Aberrant levels of mTORC1 activity have been associated with increased levels of Hypoxia inducible factor transcriptional activity, decreased autophagic activity (Land and Tee, 2007; Hands et al., 2009). There are several genes within the mTOR pathways which act as Tumour Suppressors. Mutations within these genes result in inherited genetic disorders, including Tuberous, Sclerosis complex (TSC). Loss of function of TSC1/TSC2 results in TSC which is clinically similar to BHD (Gomez et al., 1999). Arbarrant levels of mitochondrial biogeneisis and HIF activity have been observed in cells deficient in TSC1 ad TSC2 (Land and Tee, 2007; Chen et al., 2008).