Drosophila melanogaster LRPPRC2 is involved in coordination of mitochondrial translation

Baggio, Francesca; Bratić, Ana; Mourier, Arnaud; Kauppila, Timo E.S.; Tain, Luke S; Kukat, Christian; Habermann, Bianca; Partridge, Linda; Larsson, Nils‐Göran

doi:10.1093/nar/gku1132

Cited by 34 publications

(45 citation statements)

References 55 publications

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“…Nevertheless, this modulation or another yet unidentified effect of the decreased expression caused the dysfunction of the mitochondria and damaged cell morphology. Similar effects of limited modulation of mitochondrial transcripts with significant mitochondria mis-functioning have been reported for the down regulation of the mitochondrial RNA-binding proteins LRPPRC and GRSF1 ( 15 , 25 ).…”

Section: Resultssupporting

confidence: 71%

“…Because the protein is an endoribonuclease and exists as a monomer in the mitochondria, we proposed that LACTB2 plays an important role in mitochondrial gene expression. However, as with in other mitochondrial proteins involved in RNA metabolism, decreased expression of the protein and an analysis of the accumulation of mitochondrial transcripts failed to reveal its initial target ( 15 , 23 , 25 ).…”

Section: Resultsmentioning

confidence: 98%

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Identification of LACTB2, a metallo-β-lactamase protein, as a human mitochondrial endoribonuclease

et al. 2016

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Post-transcriptional control of mitochondrial gene expression, including the processing and generation of mature transcripts as well as their degradation, is a key regulatory step in gene expression in human mitochondria. Consequently, identification of the proteins responsible for RNA processing and degradation in this organelle is of great importance. The metallo-β-lactamase (MBL) is a candidate protein family that includes ribo- and deoxyribonucleases. In this study, we discovered a function for LACTB2, an orphan MBL protein found in mammalian mitochondria. Solving its crystal structure revealed almost perfect alignment of the MBL domain with CPSF73, as well as to other ribonucleases of the MBL superfamily. Recombinant human LACTB2 displayed robust endoribonuclease activity on ssRNA with a preference for cleavage after purine-pyrimidine sequences. Mutational analysis identified an extended RNA-binding site. Knockdown of LACTB2 in cultured cells caused a moderate but significant accumulation of many mitochondrial transcripts, and its overexpression led to the opposite effect. Furthermore, manipulation of LACTB2 expression resulted in cellular morphological deformation and cell death. Together, this study discovered that LACTB2 is an endoribonuclease that is involved in the turnover of mitochondrial RNA, and is essential for mitochondrial function in human cells.

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Section: Resultssupporting

confidence: 71%

Section: Resultsmentioning

confidence: 98%

Identification of LACTB2, a metallo-β-lactamase protein, as a human mitochondrial endoribonuclease

et al. 2016

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“…PTCD3 is one of the mammalian mitochondrial pentatricopeptide repeat (PPR) domain proteins ( 23 ) that play a critical role in mitochondrial translation and organelle biogenesis and maintenance ( 17 , 24 ). During carcinogenesis, the material and energy in the cells are reshaped to support and help the survival of cancer cells and to satisfy the requirements for the synthesis of biological macromolecules and energy supplement in cancer cells ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

Elevated expression of PTCD3 correlates with tumor progression and predicts poor prognosis in patients with prostate cancer

Huang

Jiang

et al. 2018

Mol Med Report

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Pentatricopeptide repeat domain protein 3 (PTCD3) is a mitochondrial RNA-binding protein that serves a role in mitochondrial translation. PTCD3 was originally reported as an oncogene that is involved in breast cancer and lymphoma. However, the expression and function of PTCD3 in prostate cancer (PCa) are unknown. Therefore, the aim of the present study was to investigate the expression of PTCD3 and its clinical significance in PCa. Immunohistochemistry and dataset analyses revealed that PTCD3 protein expression levels were enhanced in human PCa tissues and mouse PCa models. PTCD3 expression levels were positively correlated with advanced PCa pathological grade and clinical stage. Additionally, PTCD3 mRNA expression was positively correlated with tissue malignancy, high Gleason score and distant metastasis in The Cancer Genome Atlas dataset. Kaplan-Meier analysis revealed that high PTCD3 levels can predict the increased biochemical recurrence (BCR)-free survival in all patients with or without metastasis. The overexpression of PTCD3 could be used as an independent prognostic marker of poor BCR-free survival. Immunofluorescence and western blot analysis in human PCa cell lines further confirmed that PTCD3 levels were associated with the hormone independence of PCa. Therefore, the present study revealed that PTCD3 levels may serve as a novel biomarker for PCa prognosis.

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“…In mice, the LRPPRC-SLIRP complex regulates mt-mRNA stability, polyadenylation and coordinated mitochondrial translation [ 17 ]. We have also demonstrated that the bicoid stability factor (BSF, renamed DmLRPPRC1), one of the two Drosophila melanogaster orthologues of mammalian LRPPRC [ 19 , 20 ], has a very similar function as the mammalian one [ 21 ]. Furthermore, DmLRPPRC1 associates with one of the two fly orthologues of SLIRP [ 19 , 21 ], suggesting that the interaction between PPR-motif- and RRM-containing proteins is important for mitochondrial RNA metabolism and has been conserved through evolution.…”

Section: Introductionmentioning

confidence: 99%

SLIRP Regulates the Rate of Mitochondrial Protein Synthesis and Protects LRPPRC from Degradation

et al. 2015

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We have studied the in vivo role of SLIRP in regulation of mitochondrial DNA (mtDNA) gene expression and show here that it stabilizes its interacting partner protein LRPPRC by protecting it from degradation. Although SLIRP is completely dependent on LRPPRC for its stability, reduced levels of LRPPRC persist in the absence of SLIRP in vivo. Surprisingly, Slirp knockout mice are apparently healthy and only display a minor weight loss, despite a 50–70% reduction in the steady-state levels of mtDNA-encoded mRNAs. In contrast to LRPPRC, SLIRP is dispensable for polyadenylation of mtDNA-encoded mRNAs. Instead, deep RNA sequencing (RNAseq) of mitochondrial ribosomal fractions and additional molecular analyses show that SLIRP is required for proper association of mRNAs to the mitochondrial ribosome and efficient translation. Our findings thus establish distinct functions for SLIRP and LRPPRC within the LRPPRC-SLIRP complex, with a novel role for SLIRP in mitochondrial translation. Very surprisingly, our results also demonstrate that mammalian mitochondria have a great excess of transcripts under basal physiological conditions in vivo.

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Drosophila melanogaster LRPPRC2 is involved in coordination of mitochondrial translation

Cited by 34 publications

References 55 publications

Identification of LACTB2, a metallo-β-lactamase protein, as a human mitochondrial endoribonuclease

Identification of LACTB2, a metallo-β-lactamase protein, as a human mitochondrial endoribonuclease

Elevated expression of PTCD3 correlates with tumor progression and predicts poor prognosis in patients with prostate cancer

SLIRP Regulates the Rate of Mitochondrial Protein Synthesis and Protects LRPPRC from Degradation

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