Quantifying constraint in the human mitochondrial genome DOI Creative Commons
Nicole J. Lake, Wei Liu, Stephanie L. Battle

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Dec. 19, 2022

Abstract Mitochondrial DNA (mtDNA) has an important, yet often overlooked, role in health and disease. Constraint models quantify the removal of deleterious variation from population by selection, representing a powerful tool for identifying genetic underlying human phenotypes 1–4 . However, constraint model mtDNA not been developed, due to its unique features. Here we describe development mitochondrial application Genome Aggregation Database (gnomAD), large-scale dataset reporting across 56,434 humans 5 Our results demonstrate strong depletion expected variation, suggesting most variants remain undiscovered. To aid their identification, compute metrics every protein, tRNA, rRNA gene, revealing spectrum intolerance variation. We characterize constrained regions within genes via regional constraint, positions entire local showing enrichment pathogenic functionally critical sites, including topological clustering 3D protein RNA structures. Notably, identify at overlooked such as rRNAs non-coding regions. Lastly, how these can improve discovery rare common phenotypes.

Language: Английский

Mitochondrial DNA Release in Innate Immune Signaling DOI Creative Commons
Laura Newman, Gerald S. Shadel

Annual Review of Biochemistry, Journal Year: 2023, Volume and Issue: 92(1), P. 299 - 332

Published: March 31, 2023

According to the endosymbiotic theory, most of DNA original bacterial endosymbiont has been lost or transferred nucleus, leaving a much smaller (∼16 kb in mammals), circular molecule that is present-day mitochondrial (mtDNA). The ability mtDNA escape mitochondria and integrate into nuclear genome was discovered budding yeast, along with genes regulate this process. Mitochondria have emerged as key regulators innate immunity, it now recognized released cytoplasm, outside cell, circulation activates multiple immune signaling pathways. Here, we first review mechanisms through which including several inducible pores defective mitophagy autophagy. Next, cover how different forms activate specific nucleic acid sensors inflammasomes. Finally, discuss intracellular extracellular release, circulating cell-free promotes systemic inflammation, are implicated human diseases, viral infections, senescence aging.

Language: Английский

Citations

105
Mechanisms and regulation of human mitochondrial transcription DOI
Benedict G. Tan, Claes M. Gustafsson, Maria Falkenberg

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 25(2), P. 119 - 132

Published: Oct. 2, 2023

Language: Английский

Citations

42
A kinetic dichotomy between mitochondrial and nuclear gene expression processes DOI
Erik McShane, Mary Couvillion, Robert Ietswaart

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(8), P. 1541 - 1555.e11

Published: March 18, 2024

Language: Английский

Citations

25
Replication and Transcription of Human Mitochondrial DNA DOI
Maria Falkenberg, Nils‐Göran Larsson, Claes M. Gustafsson

et al.

Annual Review of Biochemistry, Journal Year: 2024, Volume and Issue: 93(1), P. 47 - 77

Published: April 10, 2024

Mammalian mitochondrial DNA (mtDNA) is replicated and transcribed by phage-like RNA polymerases, our understanding of these processes has progressed substantially over the last several decades. Molecular mechanisms have been elucidated biochemistry structural biology essential in vivo roles established cell mouse genetics. Single molecules mtDNA are packaged transcription factor A into nucleoids, their level compaction influences initiation both replication transcription. Mutations affecting molecular machineries replicating transcribing important causes human disease, reflecting critical role genome oxidative phosphorylation system biogenesis. Mechanisms controlling still need to be clarified, future research this area likely open novel therapeutic possibilities for treating dysfunction.

Language: Английский

Citations

18
Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression DOI Creative Commons
Nils Grotehans, Lynn McGarry, Hendrik Nolte

et al.

The EMBO Journal, Journal Year: 2023, Volume and Issue: 42(18)

Published: July 13, 2023

Replication of the mitochondrial genome and expression genes it encodes both depend on a sufficient supply nucleotides to mitochondria. Accordingly, dysregulated nucleotide metabolism not only destabilises genome, but also affects its transcription. Here, we report that nucleoside diphosphate kinase, NME6, supplies mitochondria with pyrimidine ribonucleotides are necessary for transcription genes. Loss NME6 function leads depletion transcripts, as well destabilisation electron transport chain impaired oxidative phosphorylation. These deficiencies rescued by an exogenous ribonucleosides. Moreover, is required maintenance DNA when access cytosolic deoxyribonucleotides limited. Our results therefore reveal important role ribonucleotide salvage in gene expression.

Language: Английский

Citations

16
Absence of both MGME1 and POLG EXO abolishes mtDNA whereas absence of either creates unique mtDNA duplications DOI

Christian D. Gonzalez,

Nadee Nissanka,

Derek Van Booven

et al.

Journal of Biological Chemistry, Journal Year: 2024, Volume and Issue: 300(4), P. 107128 - 107128

Published: March 1, 2024

Language: Английский

Citations

5
Sequence-specific dynamic DNA bending explains mitochondrial TFAM’s dual role in DNA packaging and transcription initiation DOI Creative Commons

Hyun Huh,

Jiayu Shen, Yogeeshwar Ajjugal

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 27, 2024

Abstract Mitochondrial transcription factor A (TFAM) employs DNA bending to package mitochondrial (mtDNA) into nucleoids and recruit RNA polymerase (POLRMT) at specific promoter sites, light strand (LSP) heavy (HSP). Herein, we characterize the conformational dynamics of TFAM on non-promoter sequences using single-molecule fluorescence resonance energy transfer (smFRET) protein-induced enhancement (smPIFE) methods. The DNA-TFAM complexes dynamically transition between partially fully bent states. bending/unbending rates stability are sequence-dependent—LSP forms most stable complex non-specific sequence least, which correlates with lifetimes affinities these sequences. By quantifying dynamic nature complexes, our study provides insights how acts as a multifunctional protein through states achieve specificity fidelity in while performing mtDNA packaging.

Language: Английский

Citations

5
Mitochondrial DNA copy number alterations: Key players in the complexity of glioblastoma (Review) DOI Creative Commons
Abdul Aziz Mohamed Yusoff, Siti Zulaikha Nashwa Mohd Khair, Siti Muslihah Abd Radzak

et al.

Molecular Medicine Reports, Journal Year: 2025, Volume and Issue: 31(3)

Published: Jan. 24, 2025

Renowned as a highly invasive and lethal tumor derived from neural stem cells in the central nervous system, glioblastoma (GBM) exhibits substantial histopathological variation genomic complexity, which drive its rapid progression therapeutic resistance. Alterations mitochondrial DNA (mtDNA) copy number (CN) serve crucial role GBM development progression, affecting various aspects of biology, including energy production, oxidative stress regulation cellular adaptability. Fluctuations mtDNA levels, whether elevated or diminished, can impair function, potentially disrupting phosphorylation amplifying reactive oxygen species generation, thereby fueling growth influencing treatment responses. Understanding mechanisms mtDNA‑CN variations, their interplay with genetic environmental elements microenvironment, is essential for advancing diagnostic strategies. Targeting alterations could strengthen efficacy, mitigate resistance ultimately enhance prognosis patients this aggressive brain tumor. The present review summarizes existing literature on alterations, specifically emphasizing variations association by surveying articles published between 1996 2024, sourced databases such Scopus, PubMed Google Scholar. In addition, provides brief overview genome architecture, knowledge regarding integrity CN, how mitochondria significantly impact tumorigenesis. This further presents information approaches restoring that contribute to optimized function improved health outcomes.

Language: Английский

Citations

0
TEFM facilitates transition from RNA synthesis to DNA synthesis at H-strand replication origin of mtDNA DOI Creative Commons

Shigeru Matsuda,

Masunari Nakayama,

Yura Do

et al.

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: Feb. 8, 2025

Transcription of human mitochondrial DNA (mtDNA) begins from specific transcription promoters. In strand-asynchronous mtDNA replication, transcripts the light-strand promoter serve as primers for leading-strand synthesis at origin H-strand replication (OH). A 7S strand, a presumed aborted product, is also synthesized OH. Transition RNA to OH crucial balancing with transcription, yet mechanism remains unclear. Herein, we examine role elongation factor (TEFM) in this process. TEFM knockout results decreased DNA, intermediates, and copy number, all which are concordant downregulation RNA-to-DNA transition Conversely, levels tRNAs encoded near promoters increase, indicating enhanced initiation frequency. Taken together, propose that, addition conferring processivity polymerase, plays maintaining balance between replication. Knockout factor, TEFM, cultured cells suggests protein

Language: Английский

Citations

0
Mitochondrial genetics, signalling and stress responses DOI
Yasmine J. Liu, Jonathan Sulc, Johan Auwerx

et al.

Nature Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 10, 2025

Language: Английский

Citations

0