Genome-wide quantification of RNA flow across subcellular compartments reveals determinants of the mammalian transcript life cycle

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(14), P. 2765 - 2784.e16

Published: July 1, 2024

Language: Английский

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Replication and Transcription of Human Mitochondrial DNA

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

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LRPPRC and SLIRP synergize to maintain sufficient and orderly mammalian mitochondrial translation

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(18), P. 11266 - 11282

Published: Aug. 1, 2024

Abstract In mammals, the leucine-rich pentatricopeptide repeat protein (LRPPRC) and stem-loop interacting RNA-binding (SLIRP) form a complex in mitochondrial matrix that is required throughout life cycle of most mRNAs. Although pathogenic mutations LRPPRC SLIRP genes cause devastating human diseases, vivo function corresponding proteins incompletely understood. We show here loss mice causes decrease I levels whereas other OXPHOS complexes are unaffected. generated knock-in to study interdependency by mutating specific amino acids necessary for formation. When formation disrupted, partially degraded disappears. Livers from Lrpprc had impaired translation except marked increase synthesis ATP8. Furthermore, introduction heteroplasmic mtDNA mutation (m.C5024T tRNAAla gene) into Slirp knockout an additive effect on leading embryonic lethality reduced growth mouse fibroblasts. To summarize, we report LRPPRC/SLIRP critical maintaining normal it also coordinates tissue-specific manner.

Language: Английский

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Tumor suppressor KEAP1 promotes HSPA9 degradation, controlling mitochondrial biogenesis in breast cancer

Cell Reports, Journal Year: 2024, Volume and Issue: 43(7), P. 114507 - 114507

Published: July 1, 2024

The oxidative-stress-related protein Kelch-like ECH-associated 1 (KEAP1) is a substrate articulator of E3 ubiquitin ligase, which plays an important role in the ubiquitination modification proteins. However, function KEAP1 breast cancer and its impact on survival patients with remain unclear. Our study demonstrates that KEAP1, positive prognostic factor, crucial regulating cell proliferation, apoptosis, cycle transition cancer. We investigate underlying mechanism using human tumor tissues, high-throughput detection technology, mouse xenograft model. serves as key regulator cellular metabolism, reprogramming one hallmarks tumorigenesis. has significant effect mitochondrial biogenesis oxidative phosphorylation by HSPA9 degradation. These results suggest could serve potential biomarker therapeutic target treatment

Language: Английский

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Viperin expression leads to downregulation of mitochondrial genes through misincorporation of ddhCTP by mitochondrial RNA polymerase

Journal of Biological Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108359 - 108359

Published: Feb. 1, 2025

Increasing lines of evidence link the expression interferon-stimulated gene RSAD2, encoding antiviral enzyme, viperin, to autoimmune disease. Autoimmune diseases are characterized by chronic over-production cytokines such as interferons that upregulate inflammatory response. Immune cells exposed interferon selectively downregulate transcription mitochondrially-encoded components oxidative phosphorylation system, which leads mitochondria becoming dysfunctional and impairing their ability produce ATP. But mechanism downregulation occurs has remained unknown. Here we show 3'-deoxy-3',4'-didehydrocytidine triphosphate (ddhCTP) is synthesized viperin suppresses mitochondrial causing premature chain termination when misincorporated RNA polymerase (POLRMT). We in human cell downregulates mitochondrially encoded expression. A similar effect observed across multiple ddhC, precursor ddhCTP. The pattern fits well with a simple, quantitative model describing chain-termination. In vitro measurements purified POLRMT demonstrate ddhCTP competes effectively CTP, leading its misincorporation into RNA. These findings reveal new molecular for transcriptional regulation explains reduction transcript levels response stimulation, characteristic diseases.

Language: Английский

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Mitochondrial genetics, signalling and stress responses

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

Published: March 10, 2025

Language: Английский

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Engineering mtDNA deletions by reconstituting end joining in human mitochondria

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

Published: March 1, 2025

Language: Английский

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The fate of mitochondrial respiratory complexes in aging

Trends in Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

While mitochondrial dysfunction is one of the canonical hallmarks aging, it remains only vaguely defined. Its core feature embraces defects in energy-producing molecular machinery, respiratory complexes (MRCs). The causes and consequences these hold research attention. In this review, we assess lifecycle complexes, from biogenesis to degradation, look closely at mechanisms that could underpin their aged cells. We discuss how processes be altered by aging expand on fate MRCs age-associated pathologies. Given complexity behind MRC maintenance functionality, several traits contribute phenomenon known as dysfunction. New advances will help us better understand machinery age-related diseases.

Language: Английский

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Emerging mechanisms of human mitochondrial translation regulation

Trends in Biochemical Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

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Nucleic acid sequence determinants of transcriptional pausing by human mitochondrial RNA polymerase (POLRMT)

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 26, 2025

ABSTRACT Transcription by RNA polymerase (RNAP) lies at the heart of gene expression in all organisms. The speed with which RNAPs produce is tuned part signals transcribed nucleic-acid sequences, temporarily arrange into a paused conformation unable to extend RNA. In turn, altered transcription kinetics determines three-dimensional shape ultimately folds, dictates chromatin state, and promotes or inhibits co-transcriptional events. While pause sequence determinants have been characterized for multi-subunit bacteria eukaryotic nuclei, this information lacking single-subunit RNAP human mitochondria, POLRMT. Here, we developed robust scaffold system reconstitute POLRMT vitro identified multiple transcriptional sites on mitochondrial genomic (mtDNA). Using one sequences as representative, performed suite mutational studies pinpoint elements that enhance, weaken, completely abolish pausing. Finally, search mtDNA motif revealed predicted sites, potential roles processes.

Language: Английский

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