Mitochondria in Health and Diseases

Cells, Journal Year: 2020, Volume and Issue: 9(5), P. 1177 - 1177

Published: May 9, 2020

Mitochondria are subcellular organelles evolved by endosymbiosis of bacteria with eukaryotic cells characteristics. They the main source ATP in cell and play a pivotal role life death. engaged pathogenesis human diseases aging directly or indirectly through broad range signaling pathways. However, despite an increased interest mitochondria over past decades, mechanisms mitochondria-mediated cell/organ dysfunction response to pathological stimuli remain unknown. The Special Issue, “Mitochondria Health Diseases,” organized Cells includes 24 review original articles that highlight latest achievements elucidating under physiological (healthy) conditions and, various cell/animal models patients. Altogether, Issue summarizes discusses different aspects mitochondrial metabolism function open new avenues understanding biology.

Language: Английский

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Mitochondrial dysfunction in Alzheimer's disease: Guiding the path to targeted therapies

Neurotherapeutics, Journal Year: 2025, Volume and Issue: unknown, P. e00525 - e00525

Published: Jan. 1, 2025

Language: Английский

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Mitochondria: An overview of their origin, genome, architecture, and dynamics

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2025, Volume and Issue: unknown, P. 167803 - 167803

Published: March 1, 2025

Language: Английский

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The Similarities between Human Mitochondria and Bacteria in the Context of Structure, Genome, and Base Excision Repair System

Molecules, Journal Year: 2020, Volume and Issue: 25(12), P. 2857 - 2857

Published: June 21, 2020

Mitochondria emerged from bacterial ancestors during endosymbiosis and are crucial for cellular processes such as energy production homeostasis, stress responses, cell survival, more. They the site of aerobic respiration adenosine triphosphate (ATP) in eukaryotes. However, oxidative phosphorylation (OXPHOS) is also source reactive oxygen species (ROS), which both important dangerous cell. Human mitochondria contain mitochondrial DNA (mtDNA), its integrity may be endangered by action ROS. Fortunately, human have repair mechanisms that allow protecting mtDNA repairing lesions contribute to occurrence mutations. Mutagenesis genome manifest form pathological states mitochondrial, neurodegenerative, and/or cardiovascular diseases, premature aging, cancer. The review describes structure, genome, main mechanism (base excision (BER)) context common features between bacteria. authors present a holistic view similarities bacteria show an interesting experimental model studying especially those where impaired.

Language: Английский

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ALKBH7-mediated demethylation regulates mitochondrial polycistronic RNA processing

Nature Cell Biology, Journal Year: 2021, Volume and Issue: 23(7), P. 684 - 691

Published: July 1, 2021

Language: Английский

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Mitochondrial DNA is a major source of driver mutations in cancer

Trends in cancer, Journal Year: 2022, Volume and Issue: 8(12), P. 1046 - 1059

Published: Aug. 27, 2022

Somatic mutations to mitochondrial DNA (mtDNA) in cancers are abundant, but their selection is highly gene and context dependent.Truncating tRNA mtDNA drivers certain diseases, the function of vast majority somatic variants uncharacterized.Heteroplasmic dosage likely a critical determinant phenotype produced by mutations.New techniques for single-cell profiling technologies genome editing overcome key obstacles delineating cancer. Mitochondrial among most common genetic events all tumors directly impact metabolic homeostasis. Despite central role mitochondria play energy metabolism cellular physiology, genomes has been contentious. Until recently, genomic functional studies were impeded lack adequate tumor sequencing data available methods engineering. These barriers conceptual fog surrounding have begun lift, revealing path understanding this essential cancer initiation progression. Here we discuss history, recent developments, challenges that remain oncogenetics as major new class cancer-associated unveiled.

Language: Английский

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TEFM regulates both transcription elongation and RNA processing in mitochondria

EMBO Reports, Journal Year: 2019, Volume and Issue: 20(6)

Published: April 29, 2019

Article29 April 2019Open Access Transparent process TEFM regulates both transcription elongation and RNA processing in mitochondria Shan Jiang orcid.org/0000-0003-2020-6447 Department of Medical Biochemistry Biophysics, Karolinska Institutet, Stockholm, Sweden Max Planck Institute Biology Ageing - Institutet Laboratory, Search for more papers by this author Camilla Koolmeister Jelena Misic Stefan Siira Harry Perkins Research Centre Research, The University Western Australia, Perth, WA, Australia Inge Kühl orcid.org/0000-0003-4797-0859 Mitochondrial Biology, Ageing, Cologne, Germany Integrative the Cell, UMR9198, CEA, CNRS, Paris-Sud, Université Paris-Saclay, Gif-sur-Yvette, France Eduardo Silva Ramos Maria Miranda orcid.org/0000-0002-0817-553X Min Viktor Posse Cell Gothenburg, Oleksandr Lytovchenko Ilian Atanassov orcid.org/0000-0001-8259-2545 Proteomics Core Facility, Florian A Schober Molecular Medicine Surgery, Rolf Wibom Inherited Metabolic Diseases, Hospital, Kjell Hultenby Division Clinical Centre, Laboratory Medicine, Dusanka Milenkovic Claes M Gustafsson Aleksandra Filipovska orcid.org/0000-0002-6998-8403 Nils-Göran Larsson Corresponding Author [email protected] orcid.org/0000-0001-5100-996X Information Jiang1,2, Koolmeister1,2, Misic1,2, Siira3, Kühl4,5, Ramos4, Miranda4, Jiang4, Posse6, Lytovchenko1,2, Atanassov7, Schober2,8, Wibom1,9, Hultenby10, Milenkovic4, Gustafsson6, Filipovska3 *,1,2,4,9 1Department 2Max 3Harry 4Department 5Institute 6Department 7Proteomics 8Department 9Centre 10Division *Corresponding author. Tel: +46 8 524 83036; E-mail: EMBO Reports (2019)20:e48101https://doi.org/10.15252/embr.201948101 PDFDownload PDF article text main figures. Peer ReviewDownload a summary editorial decision including letters, reviewer comments responses to feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Regulation replication expression mitochondrial DNA (mtDNA) is essential cellular energy conversion via oxidative phosphorylation. factor (TEFM) has been proposed regulate switch between termination primer formation processive, near genome-length mtDNA gene expression. Here, we report that Tefm mouse embryogenesis levels promoter-distal transcripts are drastically reduced conditional Tefm-knockout hearts. In contrast, promoter-proximal much increased knockout mice, but they mostly terminate before region where from occurs, consequently, de novo profoundly reduced. Unexpectedly, deep sequencing knockouts revealed accumulation unprocessed addition defective elongation. Furthermore, proximity-labeling (BioID) assay showed interacts with multiple factors. Our data demonstrate acts as general factor, necessary formation, loss affects mammalian mitochondria. Synopsis provides primers required also processing. embryonic development. mtDNA. Loss impairs Introduction Mitochondria harbor phosphorylation (OXPHOS) system, which performs resulting production adenosine triphosphate (ATP) 1, 2. Deficient OXPHOS well-established primary cause disease secondarily implicated variety pathophysiological conditions, such neurological disease, age-related diseases, aging 3. regulation complex because subunits respiratory chain ATP synthase encoded nuclear genome 4, 5. Mammalian gene-dense, circular double-stranded molecule, two strands defined heavy (H) light (L) strand according their base composition 6. only encodes 13 ∼90 proteins present all these addition, 2 ribosomal RNAs (mt-rRNAs) 22 transfer (mt-tRNAs), translation mRNAs (mt-mRNAs). compact contains one longer noncoding named displacement loop (D-loop), origin H (OH) promoters L (HSP LSP) located 7, 8. Transcription initiates HSP LSP generates two, genomic-length polycistronic precursor RNAs, sequentially go through yield individual (mtRNAs) initiation extensively studied using vitro vivo models, showing polymerase (POLRMT) factors (TFAM) B2 (TFB2M) core components 9-11. brief, TFAM unwinds promoter (dsDNA) introduces bubble covering site. This loose structure recruitment POLRMT enables TFB2M binding, completes assembly 12, 13. However, once successfully transcribes region, released 14, 15. Thus, initiation, not Recent studies have identified characterized another component machinery promotes processivity enable 16, 17. structures 18 complexes 19 recently determined. Binding allows form "sliding clamp" around DNA, facilitates high 19. enhances reducing duration frequencies long-lived pauses 20. initiated supplies Using recombinant previous suggested large proportion events at prematurely terminated conserved sequence block II (CSBII) within D-loop 21. occurs G-quadruplex nascent non-template be linked H-strand 22, 23. newly transcribed remains associated CSB it forms an R-loop resistant treatment RNase T1 24-26. Interestingly, reported generation human 27 helping bypass highly structured CSBII 19, 20 abolish Results study interpreted support model serves molecular coordinates balance 27, whereas argues unspecific elongator needed Processing synthesized release mature mtRNAs thought occur co-transcriptionally mainly performed distinct foci, granules 28-30. provide organizational platform spatiotemporal maturation 31. majority mt-rRNAs mt-mRNAs flanked mt-tRNAs starts excision flanking mt-tRNAs, widely accepted tRNA punctuation 32. endonucleolytic cleavage 5′- 3′-ends tRNAs P complex, consists MRPP1, MRPP2, MRPP3 33, 34 Z (ELAC2) 35, 36, respectively, situated close proximity 29, 37. G-rich binding 1 (GRSF1) can melt dsRNA 38 localized 30. Other granules, Fas-activated serine/threonine kinase (FASTK) protein family members FASTK, FASTK2 FASTKD5 39, 40, poly(A)-polymerase (mtPAP) 41, methyltransferases 42, helicases, degradosome (SUPV3L1-PNPase) 43. study, established function generating characterizing mice. We survival heart causes cardiomyopathy severe deficiency. Depletion reduces strands. there marked increase steady-state absence TEFM. At LSP, short shorter than replication. Consistently, decreased isolated lacking (RNA-Seq) northern blot analyses show assays diverse factors, (MRPP1-3), ELAC2, GRSF1, SUPV3L1-PNPase, may explain why results thus generate vivo. To determine TEFM, generated allele exon loxP sites (Fig 1A). targeted was transmitted germline, heterozygous mice (Tefm+/loxP-puro) were mated expressing flp-recombinase excise puromycin (puro) cassette obtain loxP-flanked (Tefm+/loxP). Heterozygous (Tefm+/−) obtained breeding Tefm+/loxP ubiquitously cre-recombinase (+/β-actin-cre) Intercrossing Tefm+/− produced no viable homozygous (Tefm−/−) (analyzed offspring, n = 94; Tefm+/+, 34, Tefm+/−, 60 Tefm−/−, 0), demonstrating lethality. Next, intercross analyzed staged embryos day 8.5 (E8.5; embryos, 43). All Tefm−/− genotype (n 11) small lacked structure, while Tefm+/+ 10) or 22) well developed normal appearance typical E8.5 1B). developmental defects lethality E8.5, consistent phenotype other disruption genes critical maintenance 11, 44-46. Figure 1. Disruption germline Targeting strategy gene. LoxP together selection marker (PuroR) inserted into homologous recombination. PuroR excised mating floxed Whole-body tissue-specific crossing different Morphology wild-type (Tefm+/+) Scale bar, 500 μm. level extracts 8-week-old control (L/L) (L/L, cre) 12 each group). VDAC used loading control. Survival curve (L/L; 60) cre; Heart weight body ratio 4- cre). 4 weeks: L/L L/L, cre 15; 39. Data information: (E), presented mean ± SEM. ***P < 0.001; Student's t-test. weeks 5.041476e-009, 1.096535e-033. Download figure PowerPoint leads disrupted skeletal muscle transgenic creatinine (Ckmm-cre). (TefmloxP/loxP, +/Ckmm-cre), hereafter denoted cre), born expected Mendelian ratios. depletion verified age western 1C) reverse transcriptase quantitative PCR (RT–qPCR) EV1A). had shortened life span maximal longevity 9 1D). observed progressively EV1B) enlargement EV1C–E) significant 1E). function. Click here expand figure. EV1. RT–qPCR 10 Body Representative images hearts 5 hematoxylin eosin staining morphology 100 (A–C), (A) 3,666241e-010; (B) 0.0541737, 1.126271e-016; (C) 1.207998e-006, 1.305101e-026. dysfunction Transmission electron microscopy analysis tissue end-stage alignment disorganized cristae, 2A). Quantification density 1.5-fold relative mass comparison controls EV2A). (18S rDNA) determined Southern 2B) (qPCR) EV2B) analyses. Further supporting activation biogenesis, found histone H3 blots 2B). biogenesis typically severely deficient tissues, exemplified Lrpprc Mterf4 45, 47. likely represents compensatory response seen patients 48-50. measured activities 51. drastic decrease activity I, III, IV 2C). moderate 2C), similar what models reduction 52. oxygen consumption capacity after EV2C D). Additionally, negatively affected EV2E) blue native polyacrylamide gel electrophoresis (BN-PAGE), followed blotting EV2F). OXPHOS, maintaining Knockout micrographs μm (upper panel) (lower panel). blots; 6 time-point 18S rDNA controls. (bottom loading, nucleus DNA. Respiratory spectrophotometrically normalized citrate enzyme NADH coenzyme Q reductase (complex I), cytochrome c I/III), succinate dehydrogenase II), oxidase IV). Barplot significantly changed (Benjamini-Hochberg adjusted 0.05) compared group), organized complexes. Proteins alphabetical order based on name. Boxplots intensity (LFQ) (top) (bottom). Red dot: mean; dots: value biological replicate Horizontal lines: median; box interquartile range (the first quartile (bottom) third replicates). whiskers represent maximum minimum values excluding outliers extend beyond 1.5 times range. (C), CI 4.27443E-06, CI/CIII 2.0553E-05, CII 2.76012E-05, CII/CIII 2.00732E-07, CIV 1.72156E-06. (D), (log2 [L/L, cre/L,L]) 95% confidence interval (CI). boxplot values, P-values calculated moderated t-test (limma). adj. 0.0001334 (top), 2.69E-05 EV2. A. B. Quantitative C, D. Oxygen rates Oroboros electrode Phosphorylating, non-phosphorylating, uncoupled respiration under carbonyl cyanide 3-chlorophenylhydrazone states pyruvate, glutamate, malate rotenone su

Language: Английский

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Clinical features, pathogenesis, and management of stroke-like episodes due to MELAS

Metabolic Brain Disease, Journal Year: 2021, Volume and Issue: 36(8), P. 2181 - 2193

Published: June 12, 2021

Language: Английский

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Human Mitochondrial RNA Processing and Modifications: Overview

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(15), P. 7999 - 7999

Published: July 27, 2021

Mitochondria, often referred to as the powerhouses of cells, are vital organelles that present in almost all eukaryotic organisms, including humans. They key energy suppliers site adenosine triphosphate production, and involved apoptosis, calcium homeostasis, regulation innate immune response. Abnormalities occurring mitochondria, such mitochondrial DNA (mtDNA) mutations disturbances at any stage RNA (mtRNA) processing translation, usually lead severe diseases. A fundamental line investigation is understand processes occur these their physiological consequences. Despite substantial progress has been made field mtRNA its regulation, many unknowns controversies remain. The review discusses current state knowledge human mitochondria sheds some light on unresolved issues.

Language: Английский

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Pathological and Therapeutic Advances in Parkinson’s Disease: Mitochondria in the Interplay

Journal of Alzheimer s Disease, Journal Year: 2022, Volume and Issue: 94(s1), P. S399 - S428

Published: Sept. 6, 2022

Parkinson's disease (PD) is the second most common neurodegenerative illness majorly affecting population between ages of 55 to 65 years. Progressive dopaminergic neuronal loss and collective assemblage misfolded alpha-synuclein in substantia nigra, remain notable neuro-pathological hallmarks disease. Multitudes mechanistic pathways have been proposed attempts unravel pathogenesis PD but still, it remains elusive. The convergence pathology found organelle dysfunction where mitochondria a major contributor. Mitochondrial processes like bioenergetics, mitochondrial dynamics, mitophagy are under strict regulation by genome nuclear genome. These aggravate activities upon alteration through neuroinflammation, oxidative damage, apoptosis, proteostatic stress. Therefore, grabbed central position patho-mechanistic exploration diseases PD. management challenge physicians date, due variable therapeutic response patients limitation conventional chemical agents which only offer symptomatic relief with minimal no disease-modifying effect. This review describes involved not limited protein dyshomeostasis stress, explicit attention has drawn exploring mechanisms dysfunction, primarily influence, while delineating newer exploratory targets such as GBA1, GLP, LRRK2, miRNAs targeting them.

Language: Английский

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