Mechanisms regulating mitochondrial DNA quality control DOI Open Access
Nitish Dua, Anjana Badrinarayanan

Journal of Translational Genetics and Genomics, Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 1, 2023

Maintenance of genome integrity is essential for cellular survival. There are mechanisms utilized by the cells to sense and respond assaults on genomic DNA. These conserved across all domains life collectively called DNA damage response pathways. However, eukaryotic also have extrachromosomal in mitochondria (mtDNA), which indispensable mitochondrial function, hence cell Indeed, impaired activity arising due mutations mtDNA has been found be associated with many human pathologies. Despite its importance, our understanding how ensure limited. Since do not encode machinery required maintenance their own genomes, they depend nucleus replication, transcription, repair processes. This adds a layer complexity requirement organelle crosstalk coordination damage. review summarizes recent findings that provide new insights into involved quality control, acting at level or discusses few avenues research towards comprehensive “mtDNA response”.

Language: Английский

The immune system as a driver of mitochondrial disease pathogenesis: a review of evidence DOI Creative Commons
Allison R. Hanaford, Simon C. Johnson

Orphanet Journal of Rare Diseases, Journal Year: 2022, Volume and Issue: 17(1)

Published: Sept. 2, 2022

Genetic mitochondrial diseases represent a significant challenge to human health. These are extraordinarily heterogeneous in clinical presentation and genetic origin, often involve multi-system disease with severe progressive symptoms. Mitochondrial the most common cause of inherited metabolic disorders one causes neurologic diseases, yet no proven therapeutic strategies exist. The basic cell molecular mechanisms underlying pathogenesis have not been resolved, hampering efforts develop agents.

Language: Английский

Citations

32
Roles of Mitochondrial DNA Damage in Kidney Diseases: A New Biomarker DOI Open Access
Jun Feng, Zhaowei Chen, Wei Liang

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(23), P. 15166 - 15166

Published: Dec. 2, 2022

The kidney is a mitochondria-rich organ, and diseases are recognized as mitochondria-related pathologies. Intact mitochondrial DNA (mtDNA) maintains normal function. Mitochondrial dysfunction caused by mtDNA damage, including impaired replication, mutation, leakage, methylation, involved in the progression of diseases. Herein, we review roles damage different setting diseases, acute injury (AKI) chronic disease (CKD). In variety closely associated with loss level peripheral serum urine also reflects status injury. Alleviating can promote recovery function exogenous drug treatment thus reduce short, conclude that may serve novel biomarker for assessing causes renal dysfunction, which provides new theoretical basis mtDNA-targeted intervention therapeutic option

Language: Английский

Citations

27
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
Unspliced XBP1 enhences metabolic reprogramming in colorectal cancer cells by interfering with the mitochondrial localization of MGME1 DOI
Jiandong Zhang, Suyang Zhang, Fei Yu

et al.

Biochemical and Biophysical Research Communications, Journal Year: 2025, Volume and Issue: 757, P. 151613 - 151613

Published: March 11, 2025

Language: Английский

Citations

0
Structural basis of how MGME1 processes DNA 5′ ends to maintain mitochondrial genome integrity DOI Creative Commons
Eric Mao,

H. H. Yen,

Chyuan-Chuan Wu

et al.

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(7), P. 4067 - 4078

Published: March 12, 2024

Mitochondrial genome maintenance exonuclease 1 (MGME1) helps to ensure mitochondrial DNA (mtDNA) integrity by serving as an ancillary 5'-exonuclease for polymerase γ. Curiously, MGME1 exhibits unique bidirectionality in vitro, being capable of degrading from either the 5' or 3' end. The structural basis this bidirectionally and, particularly, how it processes end assist mtDNA remain unclear. Here, we present a crystal structure human complex with 5'-overhang DNA, revealing that functions rigid clamp equipped single-strand (ss)-selective arch, allowing slide on single-stranded 5'-to-3' 3'-to-5' direction. Using nuclease activity assay, have dissected MGME1-derived cleavage patterns which arch serves ruler determine site. We also reveal displays partial DNA-unwinding ability better resolve 5'-DNA flaps, providing insights into MGME1-mediated 5'-end processing nascent mtDNA. Our study builds previously solved MGME1-DNA structures, finally comprehensive functional mechanism bidirectional, ss-specific exonuclease.

Language: Английский

Citations

2
Key Amino Acid Residues of Mitochondrial Transcription Factor A Synergize with Abasic (AP) Site Dynamics To Facilitate AP-Lyase Reactions DOI
W. R. Zhao, Wenyan Xu, Jin Tang

et al.

ACS Chemical Biology, Journal Year: 2023, Volume and Issue: 18(5), P. 1168 - 1179

Published: March 17, 2023

Human mitochondrial DNA (mtDNA) encodes 37 essential genes and plays a critical role in cellular functions. mtDNA is susceptible to damage by endogenous exogenous chemicals. Damaged molecules are counteracted the redundancy, repair, degradation of mtDNA. In response difficult-to-repair or excessive amounts lesions, crucial genome maintenance mechanism. Nevertheless, molecular basis remains incompletely understood. Recently, transcription factor A (TFAM) has emerged as degrading damaged containing abasic (AP) sites. TFAM AP-lyase activity, which cleaves at AP its homologs contain higher abundance Glu than that proteome. To decipher TFAM-catalyzed AP-DNA cleavage, we constructed variants used biochemical assays, kinetic simulations, dynamics (MD) simulations probe functional importance E187 near key residue K186. Our previous studies showed K186 primary cleave via Schiff base chemistry. Here, demonstrate facilitates β-elimination, strand scission. MD extrahelical confirmation lesion flexibility TFAM-DNA complexes facilitate reactions. Together, highly abundant Lys residues promote scission, supporting turnover implying breadth this process across different species.

Language: Английский

Citations

5
MGME1 associates with poor prognosis and is vital for cell proliferation in lower-grade glioma DOI Creative Commons
Feng Xiao, Jie Zeng, Haiyan Wang

et al.

Aging, Journal Year: 2023, Volume and Issue: 15(9), P. 3690 - 3714

Published: May 8, 2023

Mitochondrial genome maintenance exonuclease 1 (MGME1) is associated with DNA depletion, deletion, duplication, and rearrangement. However, the function of MGME1 in tumors, especially lower-grade gliomas (LGGs), has not been established.Pan-cancer analysis was used to define expression patterns prognostic value various cancers. Subsequently, we systematically determined associations between clinicopathological characteristics, prognosis, biological functions, immune genomic mutations, therapeutic responses LGGs based on their patterns. The level specific functions detected by conducting vitro experiments.Abnormally enhanced high expressions were poor prognoses including LGG. Multivariate univariate Cox regression analyses manifested that an independent biomarker for immune-related signatures, infiltration cells, checkpoint genes (ICPGs), copy number alteration (CNA), tumor mutation burden (TMB), treatment LGG patients MGME1. experiments affirmed elevated tightly connected cell proliferation cycle LGG.MGME1 closely related

Language: Английский

Citations

3
The 5′-phosphate enhances the DNA-binding and exonuclease activities of human mitochondrial genome maintenance exonuclease 1 (MGME1) DOI Creative Commons
Kathleen M. Urrutia, Wenyan Xu, Linlin Zhao

et al.

Journal of Biological Chemistry, Journal Year: 2022, Volume and Issue: 298(9), P. 102306 - 102306

Published: Aug. 5, 2022

In higher eukaryotes, mitochondria play multiple roles in energy production, signaling, and biosynthesis. Mitochondria possess copies of mitochondrial DNA (mtDNA), which encodes 37 genes that are essential for cellular function. When mtDNA is challenged by endogenous exogenous factors, undergoes repair, degradation, compensatory synthesis. degradation an emerging pathway damage response maintenance. A key factor involved the human genome maintenance exonuclease 1 (MGME1). Despite previous biochemical functional studies, controversies exist regarding polarity MGME1-mediated cleavage. Also, how sequence may affect activities MGME1 remains elusive. Such information not only fundamental to understanding but critical deciphering mechanism degradation. Herein, we use quantitative assays examine effects substrate structure on DNA-binding enzymatic MGME1. We demonstrate binds cleaves from 5'-end single-stranded substrates, especially presence 5'-phosphate, plays important role binding optimal cleavage addition, tolerates certain modifications at terminal end, such as a 5'-deoxyribosephosphate intermediate formed base excision repair. show processes different sequences with varying efficiencies, dT dC being most least efficiently digested, respectively. Our results provide insights into properties rationale coordination 3'-5' activity polymerase γ

Language: Английский

Citations

5
Mechanisms regulating mitochondrial DNA quality control DOI Open Access
Nitish Dua, Anjana Badrinarayanan,

Mr Dua

et al.

Journal of Translational Genetics and Genomics, Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 1, 2023

Maintenance of genome integrity is essential for cellular survival. There are mechanisms utilized by the cells to sense and respond assaults on genomic DNA. These conserved across all domains life collectively called DNA damage response pathways. However, eukaryotic also have extrachromosomal in mitochondria (mtDNA), which indispensable mitochondrial function, hence cell Indeed, impaired activity arising due mutations mtDNA has been found be associated with many human pathologies. Despite its importance, our understanding how ensure limited. Since do not encode machinery required maintenance their own genomes, they depend nucleus replication, transcription, repair processes. This adds a layer complexity requirement organelle crosstalk coordination damage. review summarizes recent findings that provide new insights into involved quality control, acting at level or discusses few avenues research towards comprehensive "mtDNA response".

Language: Английский

Citations

2
Recent Advances in Proteinuric Kidney Disease/Nephrotic Syndrome: Lessons from Knockout/Transgenic Mouse Models DOI Creative Commons

Ryosuke Saiki,

Kan Katayama, Kaoru Dohi

et al.

Biomedicines, Journal Year: 2023, Volume and Issue: 11(7), P. 1803 - 1803

Published: June 23, 2023

Proteinuria is known to be associated with all-cause and cardiovascular mortality, nephrotic syndrome defined by the level of proteinuria hypoalbuminemia. With advances in medicine, new causative genes for genetic kidney diseases are being discovered increasingly frequently. We reviewed articles on proteinuria/nephrotic syndrome, focal segmental glomerulosclerosis, membranous nephropathy, diabetic disease/nephropathy, hypertension/nephrosclerosis, Alport rare diseases, which have been studied mouse models. Significant progress has made understanding genetics pathophysiology thanks science, but research this area ongoing. In future, analyses patients proteinuric disease/nephrotic may ultimately lead personalized treatment options.

Language: Английский

Citations

2