The FASTK family proteins fine-tune mitochondrial RNA processing

Transcription of the human mitochondrial genome and correct processing of the two long polycistronic transcripts are crucial for oxidative phosphorylation. According to the tRNA punctuation model, nucleolytic processing of these large precursor transcripts occurs mainly through the excision of the t...

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Autores principales:	Akira Ohkubo, Lindsey Van Haute, Danielle L. Rudler, Maike Stentenbach, Florian A. Steiner, Oliver Rackham, Michal Minczuk, Aleksandra Filipovska, Jean-Claude Martinou
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/497c980462ee4337a5fb651a5b6b21d6
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spelling	oai:doaj.org-article:497c980462ee4337a5fb651a5b6b21d62021-11-25T05:53:02ZThe FASTK family proteins fine-tune mitochondrial RNA processing1553-73901553-7404https://doaj.org/article/497c980462ee4337a5fb651a5b6b21d62021-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601606/?tool=EBIhttps://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Transcription of the human mitochondrial genome and correct processing of the two long polycistronic transcripts are crucial for oxidative phosphorylation. According to the tRNA punctuation model, nucleolytic processing of these large precursor transcripts occurs mainly through the excision of the tRNAs that flank most rRNAs and mRNAs. However, some mRNAs are not punctuated by tRNAs, and it remains largely unknown how these non-canonical junctions are resolved. The FASTK family proteins are emerging as key players in non-canonical RNA processing. Here, we have generated human cell lines carrying single or combined knockouts of several FASTK family members to investigate their roles in non-canonical RNA processing. The most striking phenotypes were obtained with loss of FASTKD4 and FASTKD5 and with their combined double knockout. Comprehensive mitochondrial transcriptome analyses of these cell lines revealed a defect in processing at several canonical and non-canonical RNA junctions, accompanied by an increase in specific antisense transcripts. Loss of FASTKD5 led to the most severe phenotype with marked defects in mitochondrial translation of key components of the electron transport chain complexes and in oxidative phosphorylation. We reveal that the FASTK protein family members are crucial regulators of non-canonical junction and non-coding mitochondrial RNA processing. Author summary As a legacy of their bacterial origin, mitochondria have retained their own genome with a unique gene expression system. All mitochondrially encoded proteins are essential components of the respiratory chain. Therefore, the mitochondrial gene expression is crucial for their iconic role as the ‘powerhouse of the cell’–ATP synthesis through oxidative phosphorylation. Consistently, defects in enzymes involved in this gene expression system are a common source of incurable inherited metabolic disorders, called mitochondrial diseases. The human mitochondrial transcription generates long polycistronic transcripts that carry information for multiple genes, so that the expression level of each gene is mainly regulated through post-transcriptional events. The polycistronic transcript first undergoes RNA processing, where individual mRNA, rRNA, and tRNA are cleaved off. However, its entire molecular mechanism remains unclear, and in particular, ‘non-canonical’ RNA processing has been poorly understood. To address this question, we studied the FASTK family proteins, emerging key mitochondrial post-transcriptional regulators. We generated different human cell lines carrying single or combined disruption of FASTKD3, FASTKD4, and FASTKD5 genes, and analyzed them using biochemical and genetic approaches. We show that the FASTK family members fine-tune the processing of both ‘canonical’ and ‘non-canonical’ mitochondrial RNA junctions.Akira OhkuboLindsey Van HauteDanielle L. RudlerMaike StentenbachFlorian A. SteinerOliver RackhamMichal MinczukAleksandra FilipovskaJean-Claude MartinouPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Akira Ohkubo Lindsey Van Haute Danielle L. Rudler Maike Stentenbach Florian A. Steiner Oliver Rackham Michal Minczuk Aleksandra Filipovska Jean-Claude Martinou The FASTK family proteins fine-tune mitochondrial RNA processing
description	Transcription of the human mitochondrial genome and correct processing of the two long polycistronic transcripts are crucial for oxidative phosphorylation. According to the tRNA punctuation model, nucleolytic processing of these large precursor transcripts occurs mainly through the excision of the tRNAs that flank most rRNAs and mRNAs. However, some mRNAs are not punctuated by tRNAs, and it remains largely unknown how these non-canonical junctions are resolved. The FASTK family proteins are emerging as key players in non-canonical RNA processing. Here, we have generated human cell lines carrying single or combined knockouts of several FASTK family members to investigate their roles in non-canonical RNA processing. The most striking phenotypes were obtained with loss of FASTKD4 and FASTKD5 and with their combined double knockout. Comprehensive mitochondrial transcriptome analyses of these cell lines revealed a defect in processing at several canonical and non-canonical RNA junctions, accompanied by an increase in specific antisense transcripts. Loss of FASTKD5 led to the most severe phenotype with marked defects in mitochondrial translation of key components of the electron transport chain complexes and in oxidative phosphorylation. We reveal that the FASTK protein family members are crucial regulators of non-canonical junction and non-coding mitochondrial RNA processing. Author summary As a legacy of their bacterial origin, mitochondria have retained their own genome with a unique gene expression system. All mitochondrially encoded proteins are essential components of the respiratory chain. Therefore, the mitochondrial gene expression is crucial for their iconic role as the ‘powerhouse of the cell’–ATP synthesis through oxidative phosphorylation. Consistently, defects in enzymes involved in this gene expression system are a common source of incurable inherited metabolic disorders, called mitochondrial diseases. The human mitochondrial transcription generates long polycistronic transcripts that carry information for multiple genes, so that the expression level of each gene is mainly regulated through post-transcriptional events. The polycistronic transcript first undergoes RNA processing, where individual mRNA, rRNA, and tRNA are cleaved off. However, its entire molecular mechanism remains unclear, and in particular, ‘non-canonical’ RNA processing has been poorly understood. To address this question, we studied the FASTK family proteins, emerging key mitochondrial post-transcriptional regulators. We generated different human cell lines carrying single or combined disruption of FASTKD3, FASTKD4, and FASTKD5 genes, and analyzed them using biochemical and genetic approaches. We show that the FASTK family members fine-tune the processing of both ‘canonical’ and ‘non-canonical’ mitochondrial RNA junctions.
format	article
author	Akira Ohkubo Lindsey Van Haute Danielle L. Rudler Maike Stentenbach Florian A. Steiner Oliver Rackham Michal Minczuk Aleksandra Filipovska Jean-Claude Martinou
author_facet	Akira Ohkubo Lindsey Van Haute Danielle L. Rudler Maike Stentenbach Florian A. Steiner Oliver Rackham Michal Minczuk Aleksandra Filipovska Jean-Claude Martinou
author_sort	Akira Ohkubo
title	The FASTK family proteins fine-tune mitochondrial RNA processing
title_short	The FASTK family proteins fine-tune mitochondrial RNA processing
title_full	The FASTK family proteins fine-tune mitochondrial RNA processing
title_fullStr	The FASTK family proteins fine-tune mitochondrial RNA processing
title_full_unstemmed	The FASTK family proteins fine-tune mitochondrial RNA processing
title_sort	fastk family proteins fine-tune mitochondrial rna processing
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/497c980462ee4337a5fb651a5b6b21d6
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The FASTK family proteins fine-tune mitochondrial RNA processing

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