Mitochondrial transcription and translation: overview

D’Souza, Aaron R.; Minczuk, Michal

doi:10.1042/ebc20170102

Cited by 230 publications

(190 citation statements)

References 128 publications

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“…Clinical syndromes associated with defects in mtRNA metabolism are characterized by the variable combination of encephalopathy, myopathy, sideroblastic anemia, cardiomyopathy, hearing loss, optic atrophy, and renal or liver dysfunction (Boczonadi, Ricci, & Horvath, ; D'Souza & Minczuk, ). HCM and lactic acidosis are frequent presentations in some mitochondrial diseases related to dysfunctional mt‐tRNA maturation, such as those caused by biallelic variants in MTO1 (MIM# 614667), GTPBP3 (MIM# 608536), AARS2 (MIM# 612035) and RARS2 (MIM# 611524; Ghezzi et al, ; Gotz et al, ; Kopajtich et al, ; Lax et al, ).…”

Section: Discussionmentioning

confidence: 99%

Mutations inELAC2associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3′‐end processing

et al. 2019

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Mutations in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial respiration. Within this group, an increasing number of mutations have been identified in nuclear genes involved in mitochondrial RNA metabolism, including ELAC2. The ELAC2 gene codes for the mitochondrial RNase Z, responsible for endonucleolytic cleavage of the 3′ ends of mitochondrial pre‐tRNAs. Here, we report the identification of 16 novel ELAC2 variants in individuals presenting with mitochondrial respiratory chain deficiency, hypertrophic cardiomyopathy (HCM), and lactic acidosis. We provide evidence for the pathogenicity of the novel missense variants by studying the RNase Z activity in an in vitro system. We also modeled the residues affected by a missense mutation in solved RNase Z structures, providing insight into enzyme structure and function. Finally, we show that primary fibroblasts from the affected individuals have elevated levels of unprocessed mitochondrial RNA precursors. Our study thus broadly confirms the correlation of ELAC2 variants with severe infantile‐onset forms of HCM and mitochondrial respiratory chain dysfunction. One rare missense variant associated with the occurrence of prostate cancer (p.Arg781His) impairs the mitochondrial RNase Z activity of ELAC2, suggesting a functional link between tumorigenesis and mitochondrial RNA metabolism

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Section: Discussionmentioning

confidence: 99%

Mutations inELAC2associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3′‐end processing

et al. 2019

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“…Together, these results show that ReCappable-seq performs equally well on intact and fragmented RNA, adding further support to its high specificity for identifying 5'ends of primary RNA transcripts. (33,468) and the high confidence non-Pol-II TSS (5,269). b.…”

Section: Genome-wide Identification Of Tss In Human Lung Cellsmentioning

confidence: 99%

“…On the heavy strand, two-promoter systems (HSP1 and HSP2) have historically been proposed to explain the higher abundance of the rRNAs. However, the two promoter model remained controversial as more recent experiments [34] [35] suggest that heavy strand transcription is under the control of a single promoter (HSP1) and that the difference in abundance may be a consequence of differential turnover [33].…”

Section: Identification Of the Human Mitochondrial Tssmentioning

confidence: 99%

“…Uniquely mapped TSS are found evenly distributed across chromosomes with the notable exception of the mitochondrial genome: in total there are 18 candidate TSS positions in the mitochondrial genome (amongst them, 14 are high confidence TSS positions) defined by ReCappable-seq, from which 10 positions are located within 10 bp of the two known TSS [33] downstream of the hHSP1 (H-strand) and the hLSP (L-strand) promoters (Figure 5a). In contrast, there are 730 TSS identified by CAGE distributed across the entire mitochondrial chromosome (Figure 5a).…”

Section: B Tss Positions At Single Nucleotide Resolutionmentioning

confidence: 99%

“…In contrast, there are 730 TSS identified by CAGE distributed across the entire mitochondrial chromosome (Figure 5a). Because the number of mitochondrial TSS is known to be limited to only 2-3 TSS in the human mitochondrial genome [33], the presence of a large number of sites in the CAGE dataset is indicative of spurious TSS. Furthermore, more than half of the CAGE mitochondrial TSS (487) are located within the ribosomal genes known to be the most highly expressed locus of the mitochondrial genome.…”

Section: B Tss Positions At Single Nucleotide Resolutionmentioning

confidence: 99%

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ReCappable Seq: Comprehensive Determination of Transcription Start Sites derived from all RNA polymerases

Yan

Tzertzinis

Schildkraut

et al. 2019

Preprint

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Methodologies for determining eukaryotic Transcription Start Sites (TSS) rely on the selection of the 5’ canonical cap structure of Pol-II transcripts and are consequently ignoring entire classes of TSS derived from other RNA polymerases which play critical roles in various cell functions. To overcome this limitation, we developed ReCappable-seq and identified TSS from Pol-ll and non-Pol-II transcripts at nucleotide resolution. Applied to the human transcriptome, ReCappable-seq identifies Pol-II TSS with higher specificity than CAGE and reveals a rich landscape of TSS associated notably with Pol-III transcripts which have been previously not possible to study on a genome-wide scale. Novel TSS consistent with non-Pol-II transcripts can be found in the nuclear and mitochondrial genomes. By identifying TSS derived from all RNA-polymerases, ReCappable-seq reveals distinct epigenetic marks among Pol-lI and non-Pol-II TSS and provides a unique opportunity to concurrently interrogate the regulatory landscape of coding and non-coding RNA.

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Enhanced Oxidative Phosphorylation Driven by TACO1 Mitochondrial Translocation Promotes Stemness and Cisplatin Resistance in Bladder Cancer

Deng,

Zhou,

Chen

et al. 2024

Advanced Science

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Chemoresistance poses a critical obstacle in bladder cancer (BCa) treatment, and effective interventions are currently limited. Elevated oxidative phosphorylation (OXPHOS) has been linked to cancer stemness, a determinant of chemoresistance. However, the mechanisms underlying increased OXPHOS during cancer cell chemoresistance remain unclear. This study revealed that the mitochondrial translational activator of cytochrome oxidase subunit 1 (TACO1) is linked to stemness and cisplatin resistance in BCa cells. Mechanistically, mitochondrial TACO1 enhances the translation of the mitochondrial cytochrome c oxidase I (MTCO1), promoting mitochondrial reactive oxygen species (mtROS) by upregulating OXPHOS, consequently driving cancer stemness and cisplatin resistance. Intriguingly, the mitochondrial translocation of TACO1 is mediated by the heat shock protein 90 β (HSP90β), a process that requires circFOXK2 as a scaffold for the TACO1‐HSP90β interaction. The mutations at the binding sites of TACO1‐circFOXK2‐HSP90β disturb the ternary complex and inhibit cancer stemness and cisplatin resistance in BCa cells by suppressing the MTCO1/OXPHOS/mtROS axis. Clinically, BCa patients with increased mitochondrial TACO1 expression respond poorly to cisplatin treatment. This study elucidates the mechanisms by which TACO1 promotes BCa stemness and cisplatin resistance, providing a potential target for mitigating cisplatin resistance for BCa and a biomarker for predicting cisplatin response.

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Mitochondrial transcription and translation: overview

Cited by 230 publications

References 128 publications

Mutations inELAC2associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3′‐end processing

Mutations inELAC2associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3′‐end processing

ReCappable Seq: Comprehensive Determination of Transcription Start Sites derived from all RNA polymerases

Enhanced Oxidative Phosphorylation Driven by TACO1 Mitochondrial Translocation Promotes Stemness and Cisplatin Resistance in Bladder Cancer

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