Disruption of a mitochondrial RNA-binding protein gene results in decreased cytochrome <i>b</i> expression and a marked reduction in ubiquinol–cytochrome <i>c</i> reductase activity in mouse heart mitochondria

Xu, Fei; Ackerley, Cameron; Maj, Mary C.; Addis, Jane; Levandovskiy, Valeriy; Lee, Sang Hoon; MacKay, N.; Cameron, Jessie M.; Robinson, Brian H.

doi:10.1042/bj20080847

Cited by 80 publications

(59 citation statements)

References 28 publications

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“…The reason for this effect is not known, but it may result from transcriptional regulation and/or better adaptation to bone marrow niche conditions [15][16][17]. Overall, elevated or normal expression of the components of MRC complex I and II suggests that OXPHOS reaction and electron flow can be properly initiated, but deregulated expression of the members of MRC complex III may "derail" and/or slow down the flow of electrons causing their "leakage".…”

Section: Discussionmentioning

confidence: 99%

Chronic myeloid leukemia stem cells display alterations in expression of genes involved in oxidative phosphorylation

Flis

Irvine

Copland

et al. 2012

Leukemia & Lymphoma

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Mitochondrial respiratory chain (MRC) consists of the protein complexes I, II, III, IV, and V to carry oxidative phosphorylation (OXPHOS), which depends on electron transport to generate ATP. Electron "leakage" from MRC generates reactive oxygen species (ROS). Chronic myeloid leukemia in chronic phase (CML-CP) stem cells (LSCs) produce high levels of mitochondrial ROS causing oxidative DNA damage resulting in genomic instability generating imatinibresistant BCR-ABL1 kinase mutants and additional chromosomal aberrations. Using global mRNA microarray analysis combined with Ingenuity pathway analysis we found that LSCs display enhanced expression of genes encoding MRC complexes I, II, IV, and V. However, expression of genes encoding complex III was deregulated. Treatment with imatinib did not correct the aberrant levels of MRC genes. Therefore we postulate that abnormal expression of MRC genes may facilitate electron "leakage" to promote production of ROS and accumulation of genomic instability in LSCs in imatinib-naive and imatinib-treated patients.

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Section: Discussionmentioning

confidence: 99%

Chronic myeloid leukemia stem cells display alterations in expression of genes involved in oxidative phosphorylation

Flis

Irvine

Copland

et al. 2012

Leukemia & Lymphoma

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“…A number of proteins containing PPR domains are implicated in diseases that stem from mitochondria dysfunction. For example, leucine-rich pentatricopeptide repeat cassette (LRPPRC) and pentatricopeptide repeat domain 2 (PTCD2) are two human PPR-containing proteins that are important for the processing of mitochondrial transcripts as mutations can lead to a deficient respiratory chain (7,25).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial ribonuclease P structure provides insight into the evolution of catalytic strategies for precursor-tRNA 5′ processing

Howard¹,

Lim²,

Fierke

et al. 2012

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

110

235

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Ribonuclease P (RNase P) catalyzes the maturation of the 5′ end of tRNA precursors. Typically these enzymes are ribonucleoproteins with a conserved RNA component responsible for catalysis. However, protein-only RNase P (PRORP) enzymes process precursor tRNAs in human mitochondria and in all tRNA-using compartments of Arabidopsis thaliana. PRORP enzymes are nuclear encoded and conserved among many eukaryotes, having evolved recently as yeast mitochondrial genomes encode an RNase P RNA. Here we report the crystal structure of PRORP1 from A. thaliana at 1.75 Å resolution, revealing a prototypical metallonuclease domain tethered to a pentatricopeptide repeat (PPR) domain by a structural zinc-binding domain. The metallonuclease domain is a unique high-resolution structure of a Nedd4-BP1, YacP Nucleases (NYN) domain that is a member of the PIN domain-like fold superfamily, including the FLAP nuclease family. The structural similarity between PRORP1 and the FLAP nuclease family suggests that they evolved from a common ancestor. Biochemical data reveal that conserved aspartate residues in PRORP1 are important for catalytic activity and metal binding and that the PPR domain also enhances activity, likely through an interaction with pre-tRNA. These results provide a foundation for understanding tRNA maturation in organelles. Furthermore, these studies allow for a molecular-level comparison of the catalytic strategies used by the only known naturally evolved protein and RNA-based catalysts that perform the same biological function, pre-tRNA maturation, thereby providing insight into the differences between the prebiotic RNA world and the present protein-dominated world.catalytic mechanism | magnesium | molecular recognition A ccording to the RNA world hypothesis, RNA played dual roles as carrier of genetic information and catalyst in a prebiotic world. However, over eons of evolution, proteins with their expanded 20-aa alphabet and greater structural and functional complexity took over many RNA-based functions. Structural insights into this evolutionary transition are limited because of the lack of examples of RNA and protein macromolecules that perform the same biological function in nature. One notable exception is ribonuclease P (RNase P) that catalyzes maturation of the 5′ end of tRNA across all domains of life. Until recently, all known RNase P enzymes included a catalytic RNA component. The discovery of a protein-only RNase P [proteinacous RNase P (PRORP)] from human mitochondria and Arabidopsis thaliana has dramatically shifted this paradigm (1-3). These enzymes represent a unique class of metallonucleases and are conserved among many eukaroytes (1, 2). A. thaliana encodes three PRORP enzymes (PRORP1, -2, and -3) that catalyze pretRNA processing (2). PRORP1 localizes to the mitochondria and chloroplast whereas PRORP2 and PRORP3 localize to the nucleus (2), suggesting that protein-based enzymes catalyze pretRNA maturation in these cellular locations (2, 3). To gain mechanistic and evolutionary insights into the PRORP...

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“…2A). PTCD2 has been shown to affect Cyt b mRNA processing in the heart (Xu et al 2008). Therefore, we investigated the effect of PTCD2 knockdown on the mitochondrial lncRNAs.…”

Section: Nuclear-encoded Proteins Regulate the Levels Of Mitochondriamentioning

confidence: 99%

“…Pentatricopeptide repeat (PPR) domain protein 2 (PTCD2) belongs to the family of PPR RNA-binding proteins, which includes PTCD1 and MRPP3, and are involved in the regulation of mammalian mitochondrial gene expression , and has been found to affect the processing of the Cyt b mRNA (Xu et al 2008). We performed ss qRT-PCR on RNA isolated from purified mitochondria of HeLa cells where ELAC2, MRPP1, MRPP3, PTCD1, or PTCD2 were knocked down after 6 d to 3.5% 6 0.4, 1.6% 6 0.5, 1.9% 6 0.6, 5.3% 6 0.8, and 2.2% 6 0.5, respectively, by siRNAs and used nontargeting (NT) siRNAs as a control to determine the contribution of these proteins to the regulation and abundance of lncRNA compared with coding mRNA expression ( Fig.…”

Section: Nuclear-encoded Proteins Regulate the Levels Of Mitochondriamentioning

confidence: 99%

Long noncoding RNAs are generated from the mitochondrial genome and regulated by nuclear-encoded proteins

Rackham

Shearwood²,

Mercer³

et al. 2011

RNA

283

221

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Human mitochondrial long noncoding RNAs (lncRNAs) have not been described to date. By analysis of deep-sequencing data we have identified three lncRNAs generated from the mitochondrial genome and confirmed their expression by Northern blotting and strand-specific qRT-PCR. We show that the abundance of these lncRNAs is comparable to their complementary mRNAs and that nuclear-encoded mitochondrial proteins involved in RNA processing regulate their expression. We also identify the 59 and 39 transcript ends of the three lncRNAs and show that mitochondrial RNase P protein 1 (MRPP1) is important for the processing of these transcripts. Finally, we show that mitochondrial lncRNAs form intermolecular duplexes and that their abundance is cell-and tissue-specific, suggesting a functional role in the regulation of mitochondrial gene expression.

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Disruption of a mitochondrial RNA-binding protein gene results in decreased cytochrome b expression and a marked reduction in ubiquinol–cytochrome c reductase activity in mouse heart mitochondria

Cited by 80 publications

References 28 publications

Chronic myeloid leukemia stem cells display alterations in expression of genes involved in oxidative phosphorylation

Chronic myeloid leukemia stem cells display alterations in expression of genes involved in oxidative phosphorylation

Mitochondrial ribonuclease P structure provides insight into the evolution of catalytic strategies for precursor-tRNA 5′ processing

Long noncoding RNAs are generated from the mitochondrial genome and regulated by nuclear-encoded proteins

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