PTCD1 Is Required for 16S rRNA Maturation Complex Stability and Mitochondrial Ribosome Assembly

Perks, Kara L.; Rossetti, Giulia; Kuznetsova, Irina; Hughes, Laetitia A.; Ermer, Judith A.; Ferreira, Nicola; Busch, Jakob D.; Rudler, Danielle L.; Spåhr, Henrik; Schöndorf, Thomas; Shearwood, Ann-Marie J; Viola, Helena M.; Siira, Stefan J.; Hool, Livia C.; Milenkovic, Dusanka; Larsson, Nils-Göran; Rackham, Oliver; Filipovska, Aleksandra

doi:10.1016/j.celrep.2018.03.033

Cited by 58 publications

(60 citation statements)

References 39 publications

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“…Our observation (1) is in line with a recent molecular study of PTCD1 (Perks et al, 2018), which reported that through binding to 16S rRNA and association with FASTKD2 and RPUSD4, PTCD1 facilitates pseudouridinylation and thereby stability of 16S rRNA. Underlining its crucial role in mitoribosome assembly, we find mitoribosome biogenesis disrupted at several stages in the absence of PTCD1.…”

Section: Discussionsupporting

confidence: 90%

“…HeLa cells are able to entirely switch to glycolysis to compensate for a loss of OXPHOS (Marroquin et al, 2007) and therefore tolerate PTCD1 KO. Their lack of dependency on mitochondrial respiration is a possible reason why the absence of PTCD1 in HeLa cells did not lead to the strong compensatory transcriptional upregulation of 12S and 16S precursor RNA observed here in primary neurons and previously reported in heart and skeletal muscle (Perks et al, 2018).…”

Section: Discussionsupporting

confidence: 64%

“…We analyzed whole-exome sequencing data comparing AD patients with healthy controls, and found that a coding variant in the gene PTCD1 (pentatricopeptide repeat-containing protein 1; Rackham et al, 2009;Sanchez et al, 2011;Perks et al, 2017Perks et al, , 2018 was associated with AD in multiple cohorts. PTCD1 is an RNA binding protein that localizes to mitochondria and we show that PTCD1 is required for proper assembly of the ETC.…”

Section: Introductionmentioning

confidence: 99%

“…Complete loss of PTCD1 function is embryonic lethal in mice (Perks et al, 2017(Perks et al, , 2018 and loss of function in humans is associated with severe respiratory chain complex defects and heart failure early in life (Taylor et al, 2014). So it is not surprising that the R113W variant in PTCD1 does not present as a severe lossof-function mutation: no effect of the R113W variant on 16S rRNA levels and ATP production was observed under glucoserich conditions.…”

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confidence: 99%

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PTCD1 Is Required for Mitochondrial Oxidative-Phosphorylation: Possible Genetic Association with Alzheimer's Disease

Fleck¹,

Phu²,

Verschueren³

et al. 2019

J. Neurosci.

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In addition to amyloid-␤ plaques and tau tangles, mitochondrial dysfunction is implicated in the pathology of Alzheimer's disease (AD). Neurons heavily rely on mitochondrial function, and deficits in brain energy metabolism are detected early in AD; however, direct human genetic evidence for mitochondrial involvement in AD pathogenesis is limited. We analyzed whole-exome sequencing data of 4549 AD cases and 3332 age-matched controls and discovered that rare protein altering variants in the gene pentatricopeptide repeat-containing protein 1 (PTCD1) show a trend for enrichment in cases compared with controls. We show here that PTCD1 is required for normal mitochondrial rRNA levels, proper assembly of the mitochondrial ribosome and hence for mitochondrial translation and assembly of the electron transport chain. Loss of PTCD1 function impairs oxidative phosphorylation and forces cells to rely on glycolysis for energy production. Cells expressing the AD-linked variant of PTCD1 fail to sustain energy production under increased metabolic stress. In neurons, reduced PTCD1 expression leads to lower ATP levels and impacts spontaneous synaptic activity. Thus, our study uncovers a possible link between a protein required for mitochondrial function and energy metabolism and AD risk.Mitochondria are the main source of cellular energy and mitochondrial dysfunction is implicated in the pathology of Alzheimer's disease (AD) and other neurodegenerative disorders. Here, we identify a variant in the gene PTCD1 that is enriched in AD patients and demonstrate that PTCD1 is required for ATP generation through oxidative phosphorylation. PTCD1 regulates the level of 16S rRNA, the backbone of the mitoribosome, and is essential for mitochondrial translation and assembly of the electron transport chain. Cells expressing the AD-associated variant fail to maintain adequate ATP production during metabolic stress, and reduced PTCD1 activity disrupts neuronal energy homeostasis and dampens spontaneous transmission. Our work provides a mechanistic link between a protein required for mitochondrial function and genetic AD risk.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 64%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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PTCD1 Is Required for Mitochondrial Oxidative-Phosphorylation: Possible Genetic Association with Alzheimer's Disease

Fleck¹,

Phu²,

Verschueren³

et al. 2019

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…CEBPb, ATF4, and CHOP are also key activators of the mitochondrial unfolded protein response (mtUPR) (Higuchi-Sanabria et al, 2018;Moehle et al, 2018); however, we did not observe significant upregulation of mitochondrial proteases in the Mrps12 ep/ep mice, perhaps due to a simultaneous induction of systems that stabilize mitochondrial respiratory complexes, as we observed in these mice at 10 weeks of age. We and others have previously observed increased ATF4 and CHOP in mouse models with impaired mitochondrial translation (Rackham et al, 2016;Seiferling et al, 2016;Perks et al, 2018), and impaired mitochondrial translation can induce mtUPR in worms and mammalian cell culture (Houtkooper et al, 2013). In contrast, loss of the Lon protease in flies activates mtUPR and inhibits mitochondrial translation (Pareek et al, 2018) ◀ Figure 6.…”

Section: Of 19mentioning

confidence: 94%

Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

et al. 2019

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Translation fidelity is crucial for prokaryotes and eukaryotic nuclear‐encoded proteins; however, little is known about the role of mistranslation in mitochondria and its potential effects on metabolism. We generated yeast and mouse models with error‐prone and hyper‐accurate mitochondrial translation, and found that translation rate is more important than translational accuracy for cell function in mammals. Specifically, we found that mitochondrial mistranslation causes reduced overall mitochondrial translation and respiratory complex assembly rates. In mammals, this effect is compensated for by increased mitochondrial protein stability and upregulation of the citric acid cycle. Moreover, this induced mitochondrial stress signaling, which enables the recovery of mitochondrial translation via mitochondrial biogenesis, telomerase expression, and cell proliferation, and thereby normalizes metabolism. Conversely, we show that increased fidelity of mitochondrial translation reduces the rate of protein synthesis without eliciting a mitochondrial stress response. Consequently, the rate of translation cannot be recovered and this leads to dilated cardiomyopathy in mice. In summary, our findings reveal mammalian‐specific signaling pathways that respond to changes in the fidelity of mitochondrial protein synthesis and affect metabolism.

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Schizosaccharomyces pombe as a fundamental model for research on mitochondrial gene expression: Progress, achievements and outlooks

Dinh,

Bonnefoy

2023

IUBMB Life

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Schizosaccharomyces pombe (fission yeast) is an attractive model for mitochondrial research. The organism resembles human cells in terms of mitochondrial inheritance, mitochondrial transport, sugar metabolism, mitogenome structure and dependence of viability on the mitogenome (the petite‐negative phenotype). Transcriptions of these genomes produce only a few polycistronic transcripts, which then undergo processing as per the tRNA punctuation model. In general, the machinery for mitochondrial gene expression is structurally and functionally conserved between fission yeast and humans. Furthermore, molecular research on S. pombe is supported by a considerable number of experimental techniques and database resources. Owing to these advantages, fission yeast has significantly contributed to biomedical and fundamental research. Here, we review the current state of knowledge regarding S. pombe mitochondrial gene expression, and emphasise the pertinence of fission yeast as both a model and tool, especially for studies on mitochondrial translation.

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PTCD1 Is Required for 16S rRNA Maturation Complex Stability and Mitochondrial Ribosome Assembly

Cited by 58 publications

References 39 publications

PTCD1 Is Required for Mitochondrial Oxidative-Phosphorylation: Possible Genetic Association with Alzheimer's Disease

PTCD1 Is Required for Mitochondrial Oxidative-Phosphorylation: Possible Genetic Association with Alzheimer's Disease

Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

Schizosaccharomyces pombe as a fundamental model for research on mitochondrial gene expression: Progress, achievements and outlooks

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