Tight Control of Respiration by NADH Dehydrogenase ND5 Subunit Gene Expression in Mouse Mitochondria

Bai, Yidong; Shakeley, Rebecca M.; Attardi, Giuseppe

doi:10.1128/mcb.20.3.805-815.2000

Cited by 115 publications

(110 citation statements)

References 54 publications

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“…The mouse mtDNA-encoded proteins have been identified previously by comparing the electrophoretic patterns with human products and analysis of mouse mtDNA mutants (23)(24)(25). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

An Assembled Complex IV Maintains the Stability and Activity of Complex I in Mammalian Mitochondria

D'Aurelio

Deng

et al. 2007

Journal of Biological Chemistry

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125

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In the mammalian mitochondrial electron transfer system, the majority of electrons enter at complex I, go through complexes III and IV, and are finally delivered to oxygen. Previously we generated several mouse cell lines with suppressed expression of the nuclearly encoded subunit 4 of complex IV. This led to a loss of assembly of complex IV and its defective function. Interestingly, we found that the level of assembled complex I and its activity were also significantly reduced, whereas levels and activity of complex III were normal or up-regulated. The structural and functional dependence of complex I on complex IV was verified using a human cell line carrying a nonsense mutation in the mitochondrially encoded complex IV subunit 1 gene. Our work documents that, although there is no direct electron transfer between them, an assembled complex IV helps to maintain complex I in mammalian cells.

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Section: Resultsmentioning

confidence: 99%

An Assembled Complex IV Maintains the Stability and Activity of Complex I in Mammalian Mitochondria

D'Aurelio

Deng

et al. 2007

Journal of Biological Chemistry

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125

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“…Previous studies have established that decreasing ND5 expression corresponds with decreasing complex I-dependent respiration, suggesting that ND5 transcript levels may tightly control mitochondrial respiration rate (14).…”

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

188

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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“…This is consistent with other mtDNA-encoded structural gene mutations, 9 and is in agreement with recent findings in a mouse cell variant carrying a heteroplasmic, nonsense ND5 mutation that demonstrated exquisite control over complex Idependent respiration by this subunit. 10 This report adds to the growing number of mtDNA mutations involving complex I subunits that have recently been identified in patients with Leigh disease. One of these (G13513A) also resides in the ND5 gene and appears to cause pathology at relatively low levels of heteroplasmy.…”

Section: Discussionmentioning

confidence: 99%

Leigh disease associated with a novel mitochondrial DNA ND5 mutation

et al. 2002

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Leigh disease is a genetically heterogeneous, neurodegenerative disorder of childhood that is caused by defects of either the nuclear or mitochondrial genome. Here, we report the molecular genetic findings in a patient with neuropathological hallmarks of Leigh disease and complex I deficiency. Direct sequencing of the seven mitochondrial DNA (mtDNA)-encoded complex I (ND) genes revealed a novel missense mutation (T12706C) in the mitochondrial ND5 gene. The mutation is predicted to change an invariant amino acid in a highly conserved transmembrane helix of the mature polypeptide and was heteroplasmic in both skeletal muscle and cultured skin fibroblasts. The association of the T12706C ND5 mutation with a specific biochemical defect involving complex I is highly suggestive of a pathogenic role for this mutation.

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Tight Control of Respiration by NADH Dehydrogenase ND5 Subunit Gene Expression in Mouse Mitochondria

Cited by 115 publications

References 54 publications

An Assembled Complex IV Maintains the Stability and Activity of Complex I in Mammalian Mitochondria

An Assembled Complex IV Maintains the Stability and Activity of Complex I in Mammalian Mitochondria

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

Leigh disease associated with a novel mitochondrial DNA ND5 mutation

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