Molecular characterization of the permanent outer-inner membrane contact site of the mitochondrial genome segregation complex in trypanosomes DOI Creative Commons
Philip Stettler, Bernd Schimanski, Salome Aeschlimann

et al.

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(12), P. e1012635 - e1012635

Published: Dec. 2, 2024

The parasitic protozoan Trypanosoma brucei has a single unit mitochondrial genome linked to the basal body of flagellum via tripartite attachment complex (TAC). TAC is crucial for segregation during cytokinesis. At core TAC, outer membrane protein TAC60 binds inner p166, forming permanent contact site between two membranes. Although sites membranes are common and serve various functions, their molecular architecture remains largely unknown. This study elucidates interaction interface TAC60-p166 site. Using in silico , vitro mutational vivo analyses, we identified minimal binding segments p166. p166 consists short kinked α-helix that interacts with C-terminal Despite presence conserved charged residues either protein, electrostatic interactions not necessary formation. Instead, driven by hydrophobic effect, as converting hydrophilic amino acids disrupts

Language: Английский

Mitochondrial Dysfunction and Atherosclerosis: The Problem and the Search for Its Solution DOI Creative Commons
Ганна Володимирівна Невойт, Gediminas Jaruševičius, М. M. Potyazhenko

et al.

Biomedicines, Journal Year: 2025, Volume and Issue: 13(4), P. 963 - 963

Published: April 15, 2025

Background/Objectives: This review has been prepared to promote interest in the interdisciplinary study of mitochondrial dysfunction (MD) and atherosclerosis. aims describe state this problem indicate direction for further implementation knowledge clinical medicine. Methods: Extensive research literature was implemented elucidate role molecular mechanisms MD pathogenesis Results: A view on atherosclerosis through prism about is presented. cause primary mechanism onset progression It proposed that be considered context a continuum. Conclusions: are united by common pathogenesis. Knowledge should used argue healthy lifestyle as way prevent The development new approaches diagnosing treating an urgent task challenge modern science.

Language: Английский

Citations

0
Collective Variables and Facilitated Conformational Opening during Translocation of Human Mitochondrial RNA Polymerase (POLRMT) from Atomic Simulations DOI
Shannon J. McElhenney, Jin Yu

Journal of Chemical Theory and Computation, Journal Year: 2025, Volume and Issue: unknown

Published: April 16, 2025

Collective variable (CV) identification is challenging in complex dynamical systems. To study the translocation of a single-subunit RNA polymerase (RNAP) during human mitochondrial transcription, we employed all-atom molecular dynamics (MD) as vehicle to illustrate CV refinement conformational samplings and dimension reduction analyses. RNAP an essential mechanical step transcription elongation that dictates gene expression. The generally follows from polymerization product release proceeds initial binding or preinsertion incoming nucleotides. DNA-dependent (or POLRMT) plays critical role cellular metabolism can be key off-target design nucleotide analogue antiviral antitumor drugs due its structural similarities with many viral RNAPs RNA-dependent polymerases (RdRps). While POLRMT shares particularly high similarity bacteriophage T7 RNAP, previous experimental studies our current simulations suggest POLRMT's mechanochemical coupling mechanisms may distinct. In work, modeled complexes performed equilibrium MD on pre- post-translocation models, extensive around two potential paths (with without fingers subdomain change). We then compared time-lagged independent component analysis (tICA) neural network implementation variational approach for Markov processes (VAMPnets) dimensional methods selected atomic coordinate sets best represent sampled features simulations. Our results indicate likely coupled NTP enable opening at which would otherwise nonstabilized, translocations proceed futilely incorporation. time scale reaches over hundreds microseconds, predicted by VAMPnets Such seems match last postcatalytic kinetic suggested cycle measurements. simulation combining refinements analyses top thus variation Brownian ratcheting translocation, if motions are binding, captures transient couple sustained opening.

Language: Английский

Citations

0
Mitochondrial DNA signals driving immune responses: Why, How, Where? DOI Creative Commons
Luca Giordano, Sarah A. Ware, Claúdia Jacques Lagranha

et al.

Cell Communication and Signaling, Journal Year: 2025, Volume and Issue: 23(1)

Published: April 22, 2025

Abstract There has been a recent expansion in our understanding of DNA-sensing mechanisms. Mitochondrial dysfunction, oxidative and proteostatic stresses, instability impaired disposal nucleoids cause the release mitochondrial DNA (mtDNA) from mitochondria several human diseases, as well cell culture animal models. mislocalized to cytosol and/or extracellular compartments can trigger innate immune inflammation responses by binding receptors (DSRs). Here, we define features that make mtDNA highly immunogenic mechanisms its into compartments. We describe major DSRs bind such cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), NOD-, LRR-, PYD- domain-containing 3 receptor (NLRP3), absent melanoma 2 (AIM2) toll-like 9 (TLR9), their downstream signaling cascades. summarize key findings, novelties, gaps driving signal vascular, metabolic, kidney, lung, neurodegenerative viral bacterial infections. Finally, common strategies induce or inhibit propose challenges advance field.

Language: Английский

Citations

0
The initiation of mitochondrial DNA replication DOI Creative Commons
Yi Liu, Haibin Liu, Fan Zhang

et al.

Biochemical Society Transactions, Journal Year: 2024, Volume and Issue: 52(3), P. 1243 - 1251

Published: June 17, 2024

Mitochondrial DNA replication is initiated by the transcription of mitochondrial RNA polymerase (mtRNAP), as mitochondria lack a dedicated primase. However, mechanism determining switch between continuous and premature termination to generate primers for (mtDNA) remains unclear. The pentatricopeptide repeat domain mtRNAP exhibits exoribonuclease activity, which required initiation mtDNA in Drosophila. In this review, we explain how exonuclease activity contributes primer synthesis strand-coupled replication, discuss its regulation might co-ordinate both Drosophila mammals.

Language: Английский

Citations

1
Mitochondrial nucleoids DOI

Eve V. Kakudji,

Samantha C. Lewis

Current Biology, Journal Year: 2024, Volume and Issue: 34(21), P. R1067 - R1068

Published: Nov. 1, 2024

Language: Английский

Citations

1
A precursor of Aflatoxin B1, Versicolorin A, impairs the mitochondrial function of human intestinal Caco-2 cells DOI Creative Commons
Thierry Gauthier, Sylvie Puel,

Ophélie Rocher

et al.

Environment International, Journal Year: 2024, Volume and Issue: 193, P. 109107 - 109107

Published: Oct. 30, 2024

Versicolorin A (VERA) is a mycotoxin produced by Aspergillus section Flavi species that frequently detected in foodstuffs, particularly corn. VERA precursor of aflatoxin B

Language: Английский

Citations

0
R-Loop control and mitochondria genome stability requires the 5'-3' exonuclease/flap-endonuclease OEX1 DOI Creative Commons

Déborah Schatz-Daas,

Frédérique Weber-Lotfi, Anaïs Le Blevenec

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 6, 2024

Abstract The maintenance of the plant organelle genomes involves factors that are mostly inherited from their bacterial symbiotic ancestors. In bacteria, a major player in genome is 5-3 exonuclease/flap-endonuclease required for multiple replication and repair functions. This activity given by exonuclease domain DNA Polymerase I. Plant organellar polymerases POL1A POL1B derived Pol I, but lack this domain. Arabidopsis, proteins similar to missing were identified, named OEX1 OEX2 (Organellar Exonucleases 1 2), targeted mitochondria chloroplasts, respectively. An oex1 mutant shows severe developmental fertility defects, which aggravate subsequent generations. These defects correlate with mitochondrial (mtDNA) instability, resulting differential segregation subgenomes generated recombination, suggesting processes and/or recombination intermediates whose accumulation compromises stability. expressed two isoforms via alternative splicing, can differentially interact variably affect mtDNA repair. Recombinant digests double-strand direction has flap- endonuclease activity, key function processes. addition, high affinity RNA:DNA hybrid substrates, rapidly degrading RNA Okazaki-like structures R-loops. Consistent role suppressing R-loops, plants accumulate R-loops highly transcribed regions mtDNA. Overall, our results support fulfills important roles maintain

Language: Английский

Citations

0
Molecular characterization of the permanent outer-inner membrane contact site of the mitochondrial genome segregation complex in trypanosomes DOI Creative Commons
Philip Stettler, Bernd Schimanski, Salome Aeschlimann

et al.

PLoS Pathogens, Journal Year: 2024, Volume and Issue: 20(12), P. e1012635 - e1012635

Published: Dec. 2, 2024

The parasitic protozoan Trypanosoma brucei has a single unit mitochondrial genome linked to the basal body of flagellum via tripartite attachment complex (TAC). TAC is crucial for segregation during cytokinesis. At core TAC, outer membrane protein TAC60 binds inner p166, forming permanent contact site between two membranes. Although sites membranes are common and serve various functions, their molecular architecture remains largely unknown. This study elucidates interaction interface TAC60-p166 site. Using in silico , vitro mutational vivo analyses, we identified minimal binding segments p166. p166 consists short kinked α-helix that interacts with C-terminal Despite presence conserved charged residues either protein, electrostatic interactions not necessary formation. Instead, driven by hydrophobic effect, as converting hydrophilic amino acids disrupts

Language: Английский

Citations

0