Structural Organization and Transcription Regulation of Nuclear Genes Encoding the Mammalian Cytochrome c Oxidase Complex

Lenka, Nibedita; Vijayasarathy, Camasamudram; Mullick, Jayati; Avadhani, Narayan G.

doi:10.1016/s0079-6603(08)60830-2

Cited by 121 publications

(89 citation statements)

References 203 publications

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“…Enzymes constitute major components of the mitochondrial protein complex, and protein synthesis depends on well-coordinated transcriptional regulation of both nuclear and mitochondrial genes [28]. Cytochrome c oxidase [29] is the terminal component of the mitochondrial respiratory chain complex that catalyses the conversion of redox energy to ATP. In eukaryotes, the oligomeric enzyme is bound to the mitochondrial inner membrane with subunits ranging from seven to 13.…”

Section: Discussionmentioning

confidence: 99%

Could the low level of expression of the gene encoding skeletal muscle mitofusin-2 account for the metabolic inflexibility of obesity?

et al. 2005

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Aims/hypothesis: In obesity the cellular capacity to switch from using lipid to carbohydrate and vice versa as the energy substrate, known as 'metabolic flexibility', is impaired. Mitofusin 2 (MFN2), a mitochondrial membrane protein, seems to contribute to the maintenance and operation of the mitochondrial network, and its expression is reduced in obesity. The aim of this study was to verify whether MFN2 might be implicated in the metabolic inflexibility of obesity. Materials and methods: Insulin sensitivity was measured in six morbidly obese women before and 2 years after malabsorptive bariatric surgery (BMI 53.3±10.5 vs 30.3±4.0 kg/m 2 ). Skeletal muscle MFN2, SLC2A4 (formerly known as GLUT4), COX3 (encoding cytochrome c oxidase subunit III) and CS (encoding citrate synthase) mRNA levels were measured by real-time PCR. Results: Following biliopancreatic surgery, significant increases in MFN2 mRNA (from 0.4±0.2 to 1.7±1.1 arbitrary units [AU], p=0.019) and SLC2A4 mRNA (0.38±0.12 to 0.76±0.24 AU, p=0.04) were observed, while increases in COX3 mRNA (from 14.2±6.4 to 20.2±12.5 AU) and CS mRNA (from 0.4±0.1 to 0.7±0.3 AU) failed to reach statistical significance. Insulin-mediated whole-body glucose uptake significantly (p<0.0001) increased from 21.2±4.1 to 52.8±5.9 μmol kg fat-free mass −1 min −1 and glucose oxidation rose from 11.1±2.1 to 37.7±4.7 μmol kg fat-free mass −1 min −1 (p<0.0001). Levels of MFN2 mRNA were strongly correlated with the absolute values for the glucose oxidation rate, both during fasting (glucose oxidation =3.55 MFN2 mRNA + 3.93; R 2 =0.92, p<0.0001) and during the clamp (glucose oxidation=18.8 MFN2 mRNA+34.7; R 2 =0.80, p<0.0001). The percentage changes in MFN2 mRNA were positively correlated with the percentage change in glucose oxidation during the clamp (glucose oxidation percent (%) change=0.3 MFN2 mRNA percent (%) change +153.2; R 2 =0.61, p<0.001). Conclusions/interpretation: We propose that the significant increase in MFN2 mRNA levels may explain the increase in glucose oxidation observed in morbid obesity following bariatric surgery.

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Section: Discussionmentioning

confidence: 99%

Could the low level of expression of the gene encoding skeletal muscle mitofusin-2 account for the metabolic inflexibility of obesity?

et al. 2005

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“…This adaptive response requires the coordinated induction of a large set of nuclear genes, accomplished, at least in part, by PGC-1␣ and the transcription factors NRF-1 and NRF-2 (35,37). Because not all genes encoding mitochondrial proteins have binding sites for NRF-1 and NRF-2, additional factors must contribute to the response (37,38). Possibly, the different factors contribute selectively to mitochondrial biogenesis in different cellular contexts; e.g., the levels of NRF-1 are induced during PGC-1␣-mediated mitochondrial biogenesis in muscle but decreased when PGC-1␣ and mitochondria levels rise during brown fat development (39,40).…”

Section: Err␣ Binds To Regulatory Sites In the Promoters Of Atpsyn␤ Andmentioning

confidence: 99%

The estrogen-related receptor α (ERRα) functions in PPARγ coactivator 1α (PGC-1α)-induced mitochondrial biogenesis

Schreiber

Emter

Hock

et al. 2004

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

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500

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Estrogen-related receptor ␣ (ERR␣) is one of the first orphan nuclear receptors to be identified, yet its physiological functions are still unclear. We show here that ERR␣ is an effector of the transcriptional coactivator PGC-1␣ [peroxisome proliferator-activated receptor ␥ (PPAR␥) coactivator 1␣], and that it regulates the expression of genes involved in oxidative phosphorylation and mitochondrial biogenesis. Inhibition of ERR␣ compromises the ability of PGC-1␣ to induce the expression of genes encoding mitochondrial proteins and to increase mitochondrial DNA content. A constitutively active form of ERR␣ is sufficient to elicit both responses. ERR␣ binding sites are present in the transcriptional control regions of ERR␣͞PGC-1␣-induced genes and contribute to the transcriptional response to PGC-1␣. The ERR␣-regulated genes described here have been reported to be expressed at reduced levels in humans that are insulin-resistant. Thus, changes in ERR␣ activity could be linked to pathological changes in metabolic disease, such as diabetes. E strogen-related receptor ␣ (ERR␣, NR3B1) was identified on the basis of its sequence similarity to classical, hormoneregulated steroid receptors (1). Based on its ability to recognize similar DNA sequences as the estrogen receptors, ERR␣ has been proposed to modulate estrogen signaling (2-5). ERR␣ may also regulate bone formation, given that it is highly expressed at ossification sites, promotes osteoblast differentiation in vitro, and activates the promoter of the bone matrix protein osteopontin (6, 7). Finally, ERR␣ may regulate fatty acid oxidation. Consistent with this function, ERR␣ is prominently expressed in tissues with high capacity for ␤-oxidation of fatty acids, such as brown fat, heart, muscle, and kidney, and induces the expression of the medium-chain acyl-CoA dehydrogenase gene (8,9).A better understanding of the transcriptional programs and cellular pathways that depend on ERR␣ has been hampered by the lack of tools to regulate the activity of this receptor. Despite the high similarity between ERR␣ and other ligand-dependent nuclear receptors, it is not clear whether ERR␣ activity is regulated by small lipophilic ligands. Compounds that inhibit ERR␣-dependent transcription, such as toxaphene, chlordane, and diethylstilbestrol, have been described (10, 11). However, these compounds are not specific enough for ERR␣ to facilitate studies of its cellular function. Recently, we demonstrated that the transcriptional coactivator peroxisome proliferator-activated receptor ␥ (PPAR␥) coactivator 1␣ (PGC-1␣) regulates ERR␣ function (12). PGC-1␣ induces the expression of ERR␣ and interacts physically with ERR␣, enabling it to activate transcription (12, 13). These findings suggest that PGC-1␣ can be used as a protein ''ligand'' to regulate ERR␣-dependent transcription and study ERR␣ function.PGC-1␣ has been identified as a tissue-specific coactivator of nuclear receptors (14-16). The expression of PGC-1␣ is most prominent in tissues with high energy demands, similar to the ex...

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“…It also plays an important role in cellular homeostasis, participating in the regulation of many biological processes, such as transcription, translation, and protein translocation (1)(2)(3)(4). In particular, heme may regulate the expression of a number of nuclear genes encoding mitochondrial proteins that participate in regulatory mechanisms involving the orchestration of changes in mitochondrial biogenesis in response to different metabolic conditions (5,6).…”

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confidence: 99%

Structure and Regulated Expression of the δ-Aminolevulinate Synthase Gene from Drosophila melanogaster

Mena¹,

Fernández-Moreno²,

Börnstein³

et al. 1999

Journal of Biological Chemistry

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The structure of the single copy gene encoding the putative housekeeping isoform of Drosophila melanogaster ␦-aminolevulinate synthase (ALAS) has been determined. Southern and immunoblot analyses suggest that only the housekeeping isoform of the enzyme exists in Drosophila. We have localized a critical region for promoter activity to a sequence of 121 base pairs that contains a motif that is potentially recognized by factors of the nuclear respiratory factor-1 (NRF-1)/P3A2 family, flanked by two AP4 sites. Heme inhibits the expression of the gene by blocking the interaction of putative regulatory proteins to its 5 proximal region, a mechanism different from those proposed for other hemin-regulated promoters. Northern and in situ RNA hybridization experiments show that maternal alas mRNA is stored in the egg; its steady-state level decreases rapidly during the first hours of development and increases again after gastrulation in a period where the synthesis of several mRNAs encoding metabolic enzymes is activated. In the syncytial blastoderm, the alas mRNA is ubiquitously distributed and decreases in abundance substantially through cellular blastoderm. Late in embryonic development alas shows a specific pattern of expression, with an elevated mRNA level in oenocytes, suggesting an important role of these cells in the biosynthesis of hemoproteins in Drosophila.

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Structural Organization and Transcription Regulation of Nuclear Genes Encoding the Mammalian Cytochrome c Oxidase Complex

Cited by 121 publications

References 203 publications

Could the low level of expression of the gene encoding skeletal muscle mitofusin-2 account for the metabolic inflexibility of obesity?

Could the low level of expression of the gene encoding skeletal muscle mitofusin-2 account for the metabolic inflexibility of obesity?

The estrogen-related receptor α (ERRα) functions in PPARγ coactivator 1α (PGC-1α)-induced mitochondrial biogenesis

Structure and Regulated Expression of the δ-Aminolevulinate Synthase Gene from Drosophila melanogaster

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