Nitric Oxide-associated Protein 1 (NOA1) Is Necessary for Oxygen-dependent Regulation of Mitochondrial Respiratory Complexes

Heidler, Juliana; Al-Furoukh, Natalie; Kukat, Christian; Salwig, Isabelle; Ingelmann, Marie-Elisabeth; Seibel, Peter; Krüger, Marcus; Holtz, J.; Wittig, Ilka; Braun, Thomas; Szibor, Marten

doi:10.1074/jbc.m111.221986

Cited by 24 publications

(20 citation statements)

References 47 publications

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“…Besides encoding a REST4-like protein, E 5 -included variants overlap in opposite direction with NOA1 transcript(s), i.e., transcripts of REST and NOA1 act as natural antisense transcripts for each other, making it possible that transcripts of one gene regulate expression of the other gene through various mechanisms [44]. As a GTPase essential for mitochondrial protein synthesis, NOA1 is involved in oxidative stress and apoptosis [39], [45], [46]. Accordingly, E 5 inclusion may mediate a coordinated effect of REST and NOA1 on cellular functions.…”

Section: Discussionmentioning

confidence: 99%

Extensive Alternative Splicing of the Repressor Element Silencing Transcription Factor Linked to Cancer

Chen

Miller

2013

PLoS ONE

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The repressor element silencing transcription factor (REST) is a coordinate transcriptional and epigenetic regulator which functions as a tumor suppressor or an oncogene depending on cellular context, and a truncated splice variant REST4 has been linked to various types of cancer. We performed a comprehensive analysis of alternative splicing (AS) of REST by rapid amplification of cDNA ends and PCR amplification of cDNAs from various tissues and cell lines with specific primers. We identified 8 novel alternative exons including an alternate last exon which doubles the REST gene boundary, along with numerous 5′/3′ splice sites and ends in the constitutive exons. With the combination of various splicing patterns (e.g. exon skipping and alternative usage of the first and last exons) that are predictive of altered REST activity, at least 45 alternatively spliced variants of coding and non-coding mRNA were expressed in a species- and cell-type/tissue-specific manner with individual differences. By examining the repertoire of REST pre-mRNA splicing in 27 patients with kidney, liver and lung cancer, we found that all patients without exception showed differential expression of various REST splice variants between paired tumor and adjacent normal tissues, with striking cell-type/tissue and individual differences. Moreover, we revealed that exon 3 skipping, which causes no frame shift but loss of a domain essential for nuclear translocation, was affected by pioglitazone, a highly selective activator of the peroxisome proliferator-activated receptor gamma (PPARγ) which contributes to cell differentiation and tumorigenesis besides its metabolic actions. Accordingly, this study demonstrates an extensive AS of REST pre-mRNA which redefines REST gene boundary and structure, along with a general but differential link between REST pre-mRNA splicing and various types of cancer. These findings advance our understanding of the complex, context-dependent regulation of REST gene expression and function, and provide potential biomarkers and therapeutic targets for cancer.

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Section: Discussionmentioning

confidence: 99%

Extensive Alternative Splicing of the Repressor Element Silencing Transcription Factor Linked to Cancer

Chen

Miller

2013

PLoS ONE

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“…It is noteworthy that NOA1/C4orf14, the human homologue of yeast Mtg3, might play this role. NOA1/C4orf14 interacts with Complex IV, and the knockdown of NOA1/C4orf14 causes defects in the assembly of Complex IV and the respiratory supercomplexes containing Complex IV (40). …”

Section: Discussionmentioning

confidence: 99%

Human G-proteins, ObgH1 and Mtg1, associate with the large mitochondrial ribosome subunit and are involved in translation and assembly of respiratory complexes

Kotani

Akabane

Takeyasu

et al. 2013

Nucleic Acids Research

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The bacterial homologues of ObgH1 and Mtg1, ObgE and RbgA, respectively, have been suggested to be involved in the assembly of large ribosomal subunits. We sought to elucidate the functions of ObgH1 and Mtg1 in ribosome biogenesis in human mitochondria. ObgH1 and Mtg1 are localized in mitochondria in association with the inner membrane, and are exposed on the matrix side. Mtg1 and ObgH1 specifically associate with the large subunit of the mitochondrial ribosome in GTP-dependent manner. The large ribosomal subunit stimulated the GTPase activity of Mtg1, whereas only the intrinsic GTPase activity was detectable with ObgH1. The knockdown of Mtg1 decreased the overall mitochondrial translation activity, and caused defects in the formation of respiratory complexes. On the other hand, the depletion of ObgH1 led to the specific activation of the translation of subunits of Complex V, and disrupted its proper formation. Our results suggested that Mtg1 and ObgH1 function with the large subunit of the mitochondrial ribosome, and are also involved in both the translation and assembly of respiratory complexes. The fine coordination of ribosome assembly, translation and respiratory complex formation in mammalian mitochondria is affirmed.

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“…We recently reported a mammalian substrate of ClpXP, the mitochondrial matrix GTPase NOA1 [29][30][31][32]. We showed that increasing ClpX protein levels alone, without changing the ClpP protein level, was sufficient to significantly increase the degradation capacity of the ClpXP complex in vivo [29].…”

Section: Accepted Manuscriptmentioning

confidence: 95%

“…Controversially, we noticed a 1.7-fold up regulation after ClpX expression (Table 1). Because NOA1 is an important regulator of mitochondrial function [29][30][31][32]41], we concluded that NOA1 may be transcriptionally up regulated by the UPR mt to compensate for the parallel increase in degradation by the more active ClpXP. Therefore, we screened the noa1 gene promoter for putative CHOP binding sites [8], and we indeed found a putative CHOP consensus sequence (P1) located approximately 400 bp upstream of the initiation codon (Fig 3A).…”

Section: Chop Mediates Clpx-initiated Retrograde Transcriptional Amentioning

confidence: 96%

ClpX stimulates the mitochondrial unfolded protein response (UPRmt) in mammalian cells

Al-Furoukh

Ianni

Nolte

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Proteostasis is crucial for life and maintained by cellular chaperones and proteases. One major mitochondrial protease is the ClpXP complex, which is comprised of a catalytic ClpX subunit and a proteolytic ClpP subunit. Based on two separate observations, we hypothesized that ClpX may play a leading role in the cellular function of ClpXP. Therefore, we analyzed the effect of ClpX overexpression on a myoblast proteome by quantitative proteomics. ClpX overexpression results in the upregulation of markers of the mitochondrial proteostasis pathway, known as the "mitochondrial unfolded protein response" (UPRmt). Although this pathway is described in detail in Caenorhabditis elegans, it is not clear whether it is conserved in mammals. Therefore, we compared features of the classical nematode UPRmt with our mammalian ClpX-triggered UPRmt dataset. We show that they share the same retrograde mitochondria-to-nucleus signaling pathway that involves the key UPRmt transcription factor CHOP (also known as Ddit3, CEBPZ or GADD153). In conclusion, our data confirm the existence of a mammalian UPRmt that has great similarity to the C. elegans pathway. Furthermore, our results illustrate that ClpX overexpression is a good and simple model to study the underlying mechanisms of the UPRmt in mammalian cells.

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Nitric Oxide-associated Protein 1 (NOA1) Is Necessary for Oxygen-dependent Regulation of Mitochondrial Respiratory Complexes

Cited by 24 publications

References 47 publications

Extensive Alternative Splicing of the Repressor Element Silencing Transcription Factor Linked to Cancer

Extensive Alternative Splicing of the Repressor Element Silencing Transcription Factor Linked to Cancer

Human G-proteins, ObgH1 and Mtg1, associate with the large mitochondrial ribosome subunit and are involved in translation and assembly of respiratory complexes

ClpX stimulates the mitochondrial unfolded protein response (UPRmt) in mammalian cells

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