Human C4orf14 interacts with the mitochondrial nucleoid and is involved in the biogenesis of the small mitochondrial ribosomal subunit

He, Jin; Cooper, Helen; Reyes, Aurelio; Re, Miriam Di; Kazak, Lawrence; Wood, Stuart; Mao, Chih-Chieh; Fearnley, Ian M.; Walker, John E.; Holt, Ian

doi:10.1093/nar/gks257

Cited by 83 publications

(92 citation statements)

References 38 publications

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“…It is also known that GTPases are important for mitoribosome assembly, just as they are for bacteria (60). Human NOA1 (hNOA1), also known as MTG3 or C4orf14, is associated with the nucleoid and is necessary for SSU assembly (61)(62)(63). We have also identified ERAL1 in nucleoids (29,64).…”

Section: Discussionmentioning

confidence: 80%

Assignment of 2′-O-Methyltransferases to Modification Sites on the Mammalian Mitochondrial Large Subunit 16 S Ribosomal RNA (rRNA)

Lee

Bogenhagen

2014

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 80%

Assignment of 2′-O-Methyltransferases to Modification Sites on the Mammalian Mitochondrial Large Subunit 16 S Ribosomal RNA (rRNA)

Lee

Bogenhagen

2014

Journal of Biological Chemistry

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“…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: 91%

“…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: 98%

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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“…Currently, very little is known about how assembly of mitoribosomes is achieved, and only a few factors have been identified, which are involved in the assembly of the mt-SSU or mt-LSU (34)(35)(36)(37)(38)(39)(40)(41). Whether AFG3L2 is promoting ribosome formation or stability is at present still unclear.…”

Section: Figurementioning

confidence: 99%

AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival

Almajan¹,

Richter²,

Paeger³

et al. 2012

J. Clin. Invest.

113

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Mutations in the AFG3L2 gene have been linked to spinocerebellar ataxia type 28 and spastic ataxia-neuropathy syndrome in humans; however, the pathogenic mechanism is still unclear. AFG3L2 encodes a subunit of the mitochondrial m-AAA protease, previously implicated in quality control of misfolded inner mitochondrial membrane proteins and in regulatory functions via processing of specific substrates. Here, we used a conditional Afg3l2 mouse model that allows restricted deletion of the gene in Purkinje cells (PCs) to shed light on the pathogenic cascade in the neurons mainly affected in the human diseases. We demonstrate a cell-autonomous requirement of AFG3L2 for survival of PCs. Examination of PCs prior to neurodegeneration revealed fragmentation and altered distribution of mitochondria in the dendritic tree, indicating that abnormal mitochondrial dynamics is an early event in the pathogenic process. Moreover, PCs displayed features pointing to defects in mitochondrially encoded respiratory chain subunits at early stages. To unravel the underlying mechanism, we examined a constitutive knockout of Afg3l2, which revealed a decreased rate of mitochondrial protein synthesis associated with impaired mitochondrial ribosome assembly. We therefore propose that defective mitochondrial protein synthesis, leading to early-onset fragmentation of the mitochondrial network, is a central causative factor in AFG3L2-related neurodegeneration. IntroductionEukaryotic cells monitor the quality of their mitochondria using mechanisms acting at the interorganelle or intraorganelle level. Mitochondrial fusion and fission ensure maintenance of a functional network, whereas intramitochondrial proteases remove misfolded and aggregated proteins and also have a role in regulating mitochondrial function by processing specific substrates (1). Both levels of quality control are crucial in neurons, as emphasized by the increasing number of neurodegenerative diseases linked to impaired mitochondrial dynamics or mutations in mitochondrial proteases (1).Subunits of the matrix ATPase associated with various cellular activities (m-AAA) protease have emerged as crucial players in defending neurons against neurodegeneration. The m-AAA protease is an evolutionary conserved hexameric complex in the inner mitochondrial membrane, exposing the catalytic domains to the matrix (2, 3). Studies in yeast and mammals have shown that the m-AAA protease degrades misfolded polypeptides and excess protein components lacking assembly partners in the inner mitochondrial membrane (2,4,5). Moreover, the yeast m-AAA protease mediates proteolytic maturation of the mitochondrial ribosomal component MRPL32 (6). MRPL32 maturation is a prerequisite for mitochondrial translation and the synthesis of mitochondrially encoded (mt-encoded) respiratory chain subunits, explaining respiratory deficiencies of yeast cells lacking the m-AAA protease (6). In a reconstituted yeast system, the mammalian m-AAA protease was able to process MRPL32, suggesting evolutionary conservation of this...

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Human C4orf14 interacts with the mitochondrial nucleoid and is involved in the biogenesis of the small mitochondrial ribosomal subunit

Cited by 83 publications

References 38 publications

Assignment of 2′-O-Methyltransferases to Modification Sites on the Mammalian Mitochondrial Large Subunit 16 S Ribosomal RNA (rRNA)

Assignment of 2′-O-Methyltransferases to Modification Sites on the Mammalian Mitochondrial Large Subunit 16 S Ribosomal RNA (rRNA)

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

AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival

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