The role of the <i>LRPPRC</i> (leucine-rich pentatricopeptide repeat cassette) gene in cytochrome oxidase assembly: mutation causes lowered levels of COX (cytochrome <i>c</i> oxidase) I and COX III mRNA

Xu, Fei; Morin, Charles; Mitchell, Grant A.; Ackerley, Cameron; Robinson, Brian H.

doi:10.1042/bj20040469

Cited by 159 publications

(146 citation statements)

References 23 publications

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“…Indeed, mutations in the mitochondrial RNA binding protein, LRPPRC (leucine-rich pentatricopeptide repeat cassette) are responsible for a French Canadian form of Leigh's syndrome. In this syndrome, cytochrome c oxidase mRNAs are selectively decreased as compared with other mRNAs encoded in the mitochondrial H-strand (13).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial Cyclic AMP Response Element-binding Protein (CREB) Mediates Mitochondrial Gene Expression and Neuronal Survival

Lee

Kim

Simon

et al. 2005

Journal of Biological Chemistry

187

153

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Cyclic AMP response element-binding protein (CREB) is a widely expressed transcription factor whose role in neuronal protection is now well established. Here we report that CREB is present in the mitochondrial matrix of neurons and that it binds directly to cyclic AMP response elements (CREs) found within the mitochondrial genome. Disruption of CREB activity in the mitochondria decreases the expression of a subset of mitochondrial genes, including the ND5 subunit of complex I, down-regulates complex I-dependent mitochondrial respiration, and increases susceptibility to 3-nitropropionic acid, a mitochondrial toxin that induces a clinical and pathological phenotype similar to Huntington disease. These results demonstrate that regulation of mitochondrial gene expression by mitochondrial CREB, in part, underlies the protective effects of CREB and raise the possibility that decreased mitochondrial CREB activity contributes to the mitochondrial dysfunction and neuronal loss associated with neurodegenerative disorders.The cAMP response element-binding protein (CREB) 3 is a transcription factor known to mediate stimulus-dependent expression of genes critical for the plasticity, growth, and survival of neurons (1). A variety of stimuli alter levels of intracellular second messengers in neurons, such as cAMP and calcium, and activate CREB by leading to phosphorylation at its critical regulatory site, serine 133 (2, 3). Overexpression of constitutively active CREB prevents cell death induced by growth factor deprivation, while expression of a dominant negative form of CREB leads to apoptosis in both sympathetic neurons and cerebellar granule cells (4,5). A recent report that CREB is present in the mitochondria raises the possibility that CREB could mediate mitochondrial gene expression (6). Nonetheless, the function of mitochondrial CREB is not known. The present study confirms the presence of CREB in the mitochondria and addresses the role of CREB in mitochondrial gene expression and neuronal survival. The results raise the possibility of a novel mechanism for CREB dysfunction in the pathogenesis of neurodegenerative disorders. MATERIALS AND METHODSIsolation of Mitochondria-Mitochondria were isolated from primary cultured cortical neurons and adult rat brains by sucrose density gradient centrifugation (6).Confocal Microscopy-Indirect labeling methods were used to determine the levels of CREB, phosphorylated CREB (pCREB), and neurofilament (200 kDa) in cortical neuronal cultures and human and rat brain tissues as described previously (7).Immunogold Labeling and Electron Microscopy-Frozen samples were sectioned at Ϫ120°C, and the sections were transferred to Formvar/carboncoated copper grids. Samples were incubated with antibody in 1% bovine serum albumin for 30 min. After rinsing the samples four times with PBS, protein A-gold (10 nm) in 1% bovine serum albumin was added for 20 min. Contrasting stain procedures were carried out using 2% methyl cellulose: 3% uranyl acetate (9:1) for 10 min on ice. To dry the samples, grid...

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Section: Resultsmentioning

confidence: 99%

Mitochondrial Cyclic AMP Response Element-binding Protein (CREB) Mediates Mitochondrial Gene Expression and Neuronal Survival

Lee

Kim

Simon

et al. 2005

Journal of Biological Chemistry

187

153

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“…This finding indicates that additional activators or coactivators regulate the balance between the heavy-strand promoters or are required for full HSP2 activation. Several candidates for this role exist, including LRPPRC, which activates transcription and stabilizes existing mRNAs (13)(14)(15).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional requirements of the distal heavy-strand promoter of mtDNA

Zollo

Tiranti

Sondheimer

2012

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

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The heavy strand of mtDNA contains two promoters with nonoverlapping functions. The role of the minor heavy-strand promoter (HSP2) is controversial, because the promoter has been difficult to activate in an in vitro system. We have isolated HSP2 by excluding its interaction with the more powerful HSP1 promoter, and we find that it is transcribed efficiently by recombinant mtRNA polymerase and mitochondrial transcription factor B2. The mitochondrial transcription factor A is not required for initiation, but it has the ability to alternatively activate and repress the HSP2 transcriptional unit depending on the ratio between mitochondrial transcription factor A and other transcription factors. The positioning of transcriptional initiation agrees with our current understanding of HSP2 activity in vivo. Serial deletion of HSP2 shows that only proximal sequences are required. Several mutations, including the disruption of a polycytosine track upstream of the HSP2 initiation site, influence transcriptional activity. Transcription from HSP2 is also observed when HeLa cell mitochondrial extract is used as the source of mitochondrial polymerase, and this transcription is maintained when HSP2 is provided in proper spacing and context to the HSP1 promoter. Studies of the linked heavy-strand promoters show that they are differentially regulated by ATP dosage. We conclude that HSP2 is transcribed and has features that allow it to regulate mitochondrial mRNA synthesis.mitochondrial biology | organelle T he mitochondrial genome (mtDNA) encodes 13 proteins that are constituents of the electron transport chain and ATP synthase. Transcription of mtDNA proceeds bidirectionally, radiating out from the noncoding D-loop. The light-strand promoter (LSP) is required for the synthesis of ND6 mRNA and eight of the mitochondrial tRNAs (1). Transcription from LSP also primes the origin of heavy-strand replication, which is the first step in the synthesis of mtDNA (2).The heavy strand encodes 12 mRNAs, both mitochondrial rRNAs and the remaining tRNAs. Intracellular levels of mature rRNAs are in great excess to the mRNAs (3). Although it was initially proposed that this imbalance was caused by the existence of a single initiation site, with most primary transcripts terminating before reaching the protein coding region, later studies used a combination of ribonucleotide incorporation assays and capping of precursor transcripts to suggest the existence of two distinct heavy-strand initiation sites in close proximity (4-6). The first heavy-strand promoter (HSP1), which lies fully within the Dloop, is responsible for the synthesis of a transcript composed of the 12S and 16S rRNAs and intervening tRNAs (Fig. 1A). The minor or distal heavy-strand promoter (HSP2) initiates within the sequence of the mitochondrial tRNA for phenylalanine. HSP2-initiated transcription produces the remaining mitochondrial mRNAs by processing nearly the full length of the mtDNA.Studies of HSP2 promoter function are complicated by its unusual position, both within a tRNA-...

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“…For example, cytochrome c oxidase subunit I (COX1) an mtDNA transcript interacts with LRPPRC. 45 COX1 and mtDNA-encoded gene ATP synthase F0 subunit 6 (ATP6) were assayed by realtime Q-PCR (Table 5). MtDNA-encoded transcripts are not included on the Affymetrix U95Av2 arrays, so these transcripts were assayed by real-time Q-PCR.…”

Section: Mt Dna Copy Number and Gene Expressions Are Dysregulated In mentioning

confidence: 99%

“…47,48 Mitochondrial proteins derived from nDNA stabilize mtDNA transcripts within the mitochondria. 49 leucine-rich PPR-motif containing LRPPRC interacts to stabilize COX1, 45 and LRPPRC (increase) and COX1 (decrease) were altered in BPD, and both genes are coregulated in different tissues. 45 When LRPPRC is mutated, 24 this leads to Leigh Syndrome French Canadian (LCFS), and the transcripts and enzyme activity of COX1, as well as COX2 and COX3, are deficient owing to an alteration in the localization of LRPPRC within the mitochondria.…”

Section: Mitochondrial Dna Gene Expression In Agonal State and Mood Dmentioning

confidence: 99%

“…49 leucine-rich PPR-motif containing LRPPRC interacts to stabilize COX1, 45 and LRPPRC (increase) and COX1 (decrease) were altered in BPD, and both genes are coregulated in different tissues. 45 When LRPPRC is mutated, 24 this leads to Leigh Syndrome French Canadian (LCFS), and the transcripts and enzyme activity of COX1, as well as COX2 and COX3, are deficient owing to an alteration in the localization of LRPPRC within the mitochondria. LCFS individuals with an LRPPRC mutation present with metabolic acidosis, neurodegeneration and elevated lactate levels in CSF 50 and the disease is fatal.…”

Section: Mitochondrial Dna Gene Expression In Agonal State and Mood Dmentioning

confidence: 99%

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Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders

et al. 2006

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Mitochondrial defects in gene expression have been implicated in the pathophysiology of bipolar disorder and schizophrenia. We have now contrasted control brains with low pH versus high pH and showed that 28% of genes in mitochondrial-related pathways meet criteria for differential expression. A majority of genes in the mitochondrial, chaperone and proteasome pathways of nuclear DNA-encoded gene expression were decreased with decreased brain pH, whereas a majority of genes in the apoptotic and reactive oxygen stress pathways showed an increased gene expression with a decreased brain pH. There was a significant increase in mitochondrial DNA copy number and mitochondrial DNA gene expression with increased agonal duration. To minimize effects of agonal-pH state on mood disorder comparisons, two classic approaches were used, removing all subjects with low pH and agonal factors from analysis, or grouping low and high pH as a separate variable. Three groups of potential candidate genes emerged that may be mood disorder related: (a) genes that showed no sensitivity to pH but were differentially expressed in bipolar disorder or major depressive disorder; (b) genes that were altered by agonal-pH in one direction but altered in mood disorder in the opposite direction to agonal-pH and (c) genes with agonal-pH sensitivity that displayed the same direction of changes in mood disorder. Genes from these categories such as NR4A1 and HSPA2 were confirmed with Q-PCR. The interpretation of postmortem brain studies involving broad mitochondrial gene expression and related pathway alterations must be monitored against the strong effect of agonal-pH state. Genes with the least sensitivity to agonal-pH could present a starting point for candidate gene search in neuropsychiatric disorders. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe pathophysiology of depression and mania is largely unknown leaving open a question of which cellular pathway(s) to investigate. Gene expression screening is a powerful method for probing alterations in neural functions in mood disorder. Examining gene expression profiles has been extremely useful for establishing different phenotypes in cancer. [1][2][3] Various microarray profiles in mood disorder have been reported that use different microarray platforms, analysis methodology, regional differences, agonal factors and brain pH. [4][5][6][7][8][9][10][11][12][13][14] Presumably, a substantial heterogeneity in the pathophysiology of mood disorder coupled with small sample sizes and small fold changes contributes to the lack of consistency among the findings. 15 In five microarray studies a broad mitochondrial dysfunction was reported in neuropsychiatric disorders. 10,11,14,[16][17][18] One study of bipolar disorder (BPD) focused on a broad set of mitochondrial-related gene expression and found that in general, mitochondrial gene expression was predominantly decreased in BPD compared to controls in the dorsolateral pre-frontal cortex (DLPFC) when using Stanley samples...

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The role of the LRPPRC (leucine-rich pentatricopeptide repeat cassette) gene in cytochrome oxidase assembly: mutation causes lowered levels of COX (cytochrome c oxidase) I and COX III mRNA

Cited by 159 publications

References 23 publications

Mitochondrial Cyclic AMP Response Element-binding Protein (CREB) Mediates Mitochondrial Gene Expression and Neuronal Survival

Mitochondrial Cyclic AMP Response Element-binding Protein (CREB) Mediates Mitochondrial Gene Expression and Neuronal Survival

Transcriptional requirements of the distal heavy-strand promoter of mtDNA

Mitochondrial-related gene expression changes are sensitive to agonal-pH state: implications for brain disorders

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