Modifying the Mitochondrial Genome

Patananan, Alexander N.; Wu, Ting-Hsiang; Chiou, Pei‐Yu; Teitell, Michael A.

doi:10.1016/j.cmet.2016.04.004

Cited by 100 publications

(83 citation statements)

References 143 publications

(178 reference statements)

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“…Currently, chloroplast and mitochondrial transformation is technically very difficult, labor intensive, and time consuming and achieved only in very few organisms (58,59). It is unclear whether CRISPR/Cas9 could cleave or edit the mitochondrial genome because it is challenging to import the guide RNA component into mitochondria (60). Thus, developing chloroplast and mitochondrial RNA-targeting tools will be significant for chloroplast and mitochondrial biology.…”

Section: Discussionmentioning

confidence: 99%

PPR-SMR protein SOT1 has RNA endonuclease activity

Zhou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Numerous attempts have been made to identify and engineer sequence-specific RNA endonucleases, as these would allow for efficient RNA manipulation. However, no natural RNA endonuclease that recognizes RNA in a sequence-specific manner has been described to date. Here, we report that SUPPRESSOR OF THYLAKOID FORMATION 1 (SOT1), an Arabidopsis pentatricopeptide repeat (PPR) protein with a small MutS-related (SMR) domain, has RNA endonuclease activity. We show that the SMR moiety of SOT1 performs the endonucleolytic maturation of 23S and 4.5S rRNA through the PPR domain, specifically recognizing a 13-nucleotide RNA sequence in the 5′ end of the chloroplast 23S-4.5S rRNA precursor. In addition, we successfully engineered the SOT1 protein with altered PPR motifs to recognize and cleave a predicted RNA substrate. Our findings point to SOT1 as an exciting tool for RNA manipulation.photosynthesis | PPR-SMR protein | RNA endonuclease | rRNA biogenesis S equence-specific RNA endonucleases are crucial to establishing RNA manipulation technology (1). Compared with DNA editing, RNA manipulation could be more useful and reversible because it does not result in permanent changes to the genome. In addition, sequence-specific RNA endonucleases could potentially be used as an RNA silencing tool to complement RNAi, because RNAi is sometimes ineffective in certain organisms and RNAi machinery is not present in cellular compartments such as chloroplasts and mitochondria. Despite extensive investigations, a natural RNA endonuclease that recognizes RNA in an intrinsic sequence-specific manner has not yet been identified.Pentatricopeptide repeat (PPR) proteins exist in eukaryotes, have greatly expanded in terrestrial plants, and take part in most RNA metabolic processes in organelles (2-5). The PPR domain can specifically recognize RNAs in an intrinsic sequence-specific manner (5-8). The 2nd, 5th, and 35th (or 1st, 4th, and 34th or 3rd, 6th, and 1st in other numbering systems) residues at each repeat are considered to be RNA selection "codes" (9-11). Based on these codes, several PPR proteins have been successfully modified to recognize predictable RNA targets (9,(12)(13)(14)(15)(16)(17).The small MutS-related (SMR) domain was originally identified at the C terminus of MutS2 in the cyanobacterium Synechocystis (18). SMR proteins are widely distributed in almost all organisms (19). Recent studies demonstrated the SMR domain exhibits DNA nicking nuclease activity in vitro (20-25). Furthermore, a C-terminal SMR domain in Leishmania donovani S-phase mRNA cycling sequence binding protein (CSBP) has RNA cleavage activity in vitro (26). These findings suggest that the SMR domain has nuclease activity.Interestingly, a small protein family containing both PPR and SMR domains was recently described (27). PPR-SMR proteins are found mainly in land plants. Arabidopsis thaliana contains eight PPR-SMR proteins localized to the organelles, including mitochondria and chloroplasts (27). Currently, four PPR-SMR proteins have been characterized. They play ...

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Section: Discussionmentioning

confidence: 99%

PPR-SMR protein SOT1 has RNA endonuclease activity

Zhou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Altered energy metabolism is now regarded as one of the hallmarks of cancer (Koppenol et al, 2011; Hanahan and Weinberg, 2011; Vyas et al, 2016). In this context, the mitochondrial genome has been reported to play a role in tumorigenesis (Lee and St John, 2016; Patananan et al, 2016) and in metastatic cancer (Ishikawa et al, 2008; Hayashi et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells

Dong

Kovářová

Bajzíková

et al. 2017

eLife

220

188

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Recently, we showed that generation of tumours in syngeneic mice by cells devoid of mitochondrial (mt) DNA (ρ0 cells) is linked to the acquisition of the host mtDNA. However, the mechanism of mtDNA movement between cells remains unresolved. To determine whether the transfer of mtDNA involves whole mitochondria, we injected B16ρ0 mouse melanoma cells into syngeneic C57BL/6Nsu9-DsRed2 mice that express red fluorescent protein in their mitochondria. We document that mtDNA is acquired by transfer of whole mitochondria from the host animal, leading to normalisation of mitochondrial respiration. Additionally, knockdown of key mitochondrial complex I (NDUFV1) and complex II (SDHC) subunits by shRNA in B16ρ0 cells abolished or significantly retarded their ability to form tumours. Collectively, these results show that intact mitochondria with their mtDNA payload are transferred in the developing tumour, and provide functional evidence for an essential role of oxidative phosphorylation in cancer.DOI: http://dx.doi.org/10.7554/eLife.22187.001

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“…Mitochondrial DNA (mtDNA) mutations and polymorphisms contribute to many complex diseases, including atherosclerosis (9), Alzheimer’s disease (10, 11), diabetes (12), obesity (13), aging (5), and cancer (8, 14, 15). Although the mechanisms responsible remain mostly unknown, we hypothesized that there are differential mtDNA-driven changes in nuclear (n)DNA expression and DNA methylation, since retrograde and anterograde communication exist between the nuclear and mitochondrial genomes.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Genomic Backgrounds Affect Nuclear DNA Methylation and Gene Expression

et al. 2017

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Mitochondrial DNA (mtDNA) mutations and polymorphisms contribute to many complex diseases, including cancer. Using a unique mouse model that contains nDNA from one mouse strain and homoplasmic mitochondrial haplotypes from different mouse strain(s) - designated Mitochondrial Nuclear Exchange (MNX) – we showed that mtDNA could alter mammary tumor metastasis. Since retrograde and anterograde communication exist between the nuclear and mitochondrial genomes, we hypothesized that there are differential mtDNA-driven changes in nuclear (n)DNA expression and DNA methylation. Genome-wide nDNA methylation and gene expression were measured in harvested brain tissue from paired wild-type and MNX mice. Selective differential DNA methylation and gene expression were observed between strains having identical nDNA, but different mtDNA. These observations provide insights into how mtDNA could be altering epigenetic regulation and thereby contribute to the pathogenesis of metastasis.

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Modifying the Mitochondrial Genome

Cited by 100 publications

References 143 publications

PPR-SMR protein SOT1 has RNA endonuclease activity

PPR-SMR protein SOT1 has RNA endonuclease activity

Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells

Mitochondrial Genomic Backgrounds Affect Nuclear DNA Methylation and Gene Expression

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