C7orf30 specifically associates with the large subunit of the mitochondrial ribosome and is involved in translation

Wanschers, Bas F.J.; Szklarczyk, Radek; Pajak, Aleksandra; Brand, Mariël A.M. van den; Gloerich, Jolein; Rodenburg, Richard J.; Lightowlers, Robert N.; Nijtmans, Leo; Huynen, Martijn A.

doi:10.1093/nar/gkr1271

Cited by 48 publications

(52 citation statements)

References 54 publications

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“…For instance, many of the proteins linked to mitochondrial ribosomal biogenesis and assembly have clear bacterial homologs and orthologs (13,31,32,34,36–38). In contrast, MPV17L2 does not appear to have any bacterial counterpart linked to protein synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…The association of MPV17L2 with the mtLSU on SGs and its immunoprecipitation with ICT1 are features shared with C7orf30 (31,32), a protein which has been proposed to participate in the assembly of the mtLSU (33). Moreover, MPV17L2 silencing induced a marked depletion of C7orf30 (Figure 6C), and the effects of C7orf30 gene silencing display considerable overlap with those reported here for MPV17L2.…”

Section: Discussionmentioning

confidence: 99%

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MPV17L2 is required for ribosome assembly in mitochondria

Rosa¹,

Durigon²,

Pearce

et al. 2014

Nucleic Acids Res

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MPV17 is a mitochondrial protein of unknown function, and mutations in MPV17 are associated with mitochondrial deoxyribonucleic acid (DNA) maintenance disorders. Here we investigated its most similar relative, MPV17L2, which is also annotated as a mitochondrial protein. Mitochondrial fractionation analyses demonstrate MPV17L2 is an integral inner membrane protein, like MPV17. However, unlike MPV17, MPV17L2 is dependent on mitochondrial DNA, as it is absent from ρ0 cells, and co-sediments on sucrose gradients with the large subunit of the mitochondrial ribosome and the monosome. Gene silencing of MPV17L2 results in marked decreases in the monosome and both subunits of the mitochondrial ribosome, leading to impaired protein synthesis in the mitochondria. Depletion of MPV17L2 also induces mitochondrial DNA aggregation. The DNA and ribosome phenotypes are linked, as in the absence of MPV17L2 proteins of the small subunit of the mitochondrial ribosome are trapped in the enlarged nucleoids, in contrast to a component of the large subunit. These findings suggest MPV17L2 contributes to the biogenesis of the mitochondrial ribosome, uniting the two subunits to create the translationally competent monosome, and provide evidence that assembly of the small subunit of the mitochondrial ribosome occurs at the nucleoid.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MPV17L2 is required for ribosome assembly in mitochondria

Rosa¹,

Durigon²,

Pearce

et al. 2014

Nucleic Acids Res

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“…Moreover, C7orf30, a member of the DUF143 family of ribosomal silencing factors, participates in mtLSU assembly [131][132][133] by interacting with uL14 and promoting its incorporation into the mtLSU [132]. Knockdown of C7orf30 by short hairpin RNA (shRNA) does not alter the sedimentation profile of the mtLSU, but results in mtLSU depletion and consequent decreased monosome formation that leads to a mitochondrial translation defect.…”

Section: Other Mitoribosome Assembly Factorsmentioning

confidence: 99%

Mitochondrial ribosome assembly in health and disease

et al. 2015

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The ribosome is a structurally and functionally conserved macromolecular machine universally responsible for catalyzing protein synthesis. Within eukaryotic cells, mitochondria contain their own ribosomes (mitoribosomes), which synthesize a handful of proteins, all essential for the biogenesis of the oxidative phosphorylation system. High-resolution cryo-EM structures of the yeast, porcine and human mitoribosomal subunits and of the entire human mitoribosome have uncovered a wealth of new information to illustrate their evolutionary divergence from their bacterial ancestors and their adaptation to synthesis of highly hydrophobic membrane proteins. With such structural data becoming available, one of the most important remaining questions is that of the mitoribosome assembly pathway and factors involved. The regulation of mitoribosome biogenesis is paramount to mitochondrial respiration, and thus to cell viability, growth and differentiation. Moreover, mutations affecting the rRNA and protein components produce severe human mitochondrial disorders. Despite its biological and biomedical significance, knowledge on mitoribosome biogenesis and its deviations from the much-studied bacterial ribosome assembly processes is scarce, especially the order of rRNA processing and assembly events and the regulatory factors required to achieve fully functional particles. This article focuses on summarizing the current available information on mitoribosome assembly pathway, factors that form the mitoribosome assembly machinery, and the effect of defective mitoribosome assembly on human health.

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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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C7orf30 specifically associates with the large subunit of the mitochondrial ribosome and is involved in translation

Cited by 48 publications

References 54 publications

MPV17L2 is required for ribosome assembly in mitochondria

MPV17L2 is required for ribosome assembly in mitochondria

Mitochondrial ribosome assembly in health and disease

AFG3L2 supports mitochondrial protein synthesis and Purkinje cell survival

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