Mitochondrial Protein Synthesis Adapts to Influx of Nuclear-Encoded Protein

Richter‐Dennerlein, Ricarda; Oeljeklaus, Silke; Lorenzi, Isotta; Ronsör, Christin; Bareth, Bettina; Schendzielorz, Alexander Benjamin; Wang, Cong; Warscheid, Bettina; Rehling, Peter; Dennerlein, Sven

doi:10.1016/j.cell.2016.09.003

Cited by 179 publications

(229 citation statements)

References 62 publications

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“…In addition, we identified components of the mitochondrial ribosomal large (uL1m) and the small (mS40) subunits and the insertase OXA1L as MITRAC15-associated proteins. These observations are in agreement with a function of MITRAC15 during the ND2 translation process similar to C12ORF62 during COX1 synthesis [18]. In contrast, an immunoisolation of ACAD9 FLAG did not co-purify the MITRAC component MITRAC12 but recovered MITRAC15 and TIM21 ( Fig 2D).…”

Section: Functional Segregation Of Mitrac15 Into Assembly Modulessupporting

confidence: 88%

“…In human mitochondria, the assembly of COX1 occurs through an intermediate termed MITRAC complex (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase) [18][19][20]. Therefore, these proteins represent translational regulators of COX1 [18,19,21,22]. Therefore, these proteins represent translational regulators of COX1 [18,19,21,22].…”

Section: Introductionmentioning

confidence: 99%

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MITRAC15/COA1 promotes mitochondrial translation in a ND2 ribosome–nascent chain complex

et al. 2019

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The mitochondrial genome encodes for thirteen core subunits of the oxidative phosphorylation system. These proteins assemble with imported proteins in a modular manner into stoichiometric enzyme complexes. Assembly factors assist in these biogenesis processes by providing co-factors or stabilizing transient assembly stages. However, how expression of the mitochondrial-encoded subunits is regulated to match the availability of nuclear-encoded subunits is still unresolved. Here, we address the function of MITRAC15/COA1, a protein that participates in complex I biogenesis and complex IV biogenesis. Our analyses of a MITRAC15 knockout mutant reveal that MITRAC15 is required for translation of the mitochondrial-encoded complex I subunit ND2. We find that MITRAC15 is a constituent of a ribosome-nascent chain complex during ND2 translation. Chemical crosslinking analyses demonstrate that binding of the ND2-specific assembly factor ACAD9 to the ND2 polypeptide occurs at the C-terminus and thus downstream of MITRAC15. Our analyses demonstrate that expression of the founder subunit ND2 of complex I undergoes regulation. Moreover, a ribosome-nascent chain complex with MITRAC15 is at the heart of this process.

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Section: Functional Segregation Of Mitrac15 Into Assembly Modulessupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

MITRAC15/COA1 promotes mitochondrial translation in a ND2 ribosome–nascent chain complex

et al. 2019

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“…COX2 synthesis has been reported to be decreased in fibroblasts from patients with mutations in SCO2 but not in SCO1 (26). However, it is not affected in HEK293T cells knocked out for either COX20 (5) or COX18 (this work) or knocked down for SCO2 (27). Cell type-specific effects could Figure 6.…”

Section: Discussionmentioning

confidence: 83%

Human mitochondrial cytochrome c oxidase assembly factor COX18 acts transiently as a membrane insertase within the subunit 2 maturation module

Bourens¹,

Barrientos

2017

Journal of Biological Chemistry

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Edited by John M. Denu Defects in mitochondrial cytochrome c oxidase or respiratory chain complex IV (CIV) assembly are a frequent cause of human mitochondrial disorders. Specifically, mutations in four conserved assembly factors impinging the biogenesis of the mitochondrion-encoded catalytic core subunit 2 (COX2) result in myopathies. These factors afford stability of newly synthesized COX2 (the dystonia-ataxia syndrome protein COX20), a protein with two transmembrane domains, and maturation of its copper center, Cu A (cardiomyopathy proteins SCO1, SCO2, and COA6). COX18 is an additional COX2 assembly factor that belongs to the Oxa1 family of membrane protein insertases. Here, we used a gene-editing approach to generate a human COX18 knock-out HEK293T cell line that displays isolated complete CIV deficiency. We demonstrate that COX20 stabilizes COX2 during insertion of its N-proximal transmembrane domain, and subsequently, COX18 transiently interacts with COX2 to promote translocation across the inner membrane of the COX2 C-tail that contains the apo-Cu A site. The release of COX18 from this complex coincides with the binding of the SCO1-SCO2-COA6 copper metallation module to COX2-COX20 to finalize COX2 biogenesis. Therefore, COX18 is a new candidate when screening for mitochondrial disorders associated with isolated CIV deficiency.In nucleated human cells, mitochondria are central organelles that harbor the enzymes required for cellular respiration and aerobic energy production through oxidative phosphorylation (OXPHOS).2 These multimeric complexes are formed by subunits encoded in the nuclear and mitochondrial genomes that are assembled into functional units with the assistance of a myriad of nucleus-encoded ancillary proteins, generally called assembly factors. Mutations in OXPHOS subunits or assembly factors result in failure to fulfill the energy demands of most tissues with a major incidence in those with high energy

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“…Despite its extraordinarily high sequence variability, which has been used to map human evolution (1–3), mtDNA has been traditionally thought to be relatively innocuous (4). Recent evidence strongly demonstrates that naturally occurring mtDNA polymorphisms are not neutral, and that mtDNA-nDNA interactions profoundly affect mammalian biology (5, 6) and contribute to some pathologies (7, 8). …”

Section: Introductionmentioning

confidence: 99%

“…Intuitively, retrograde communication from the mitochondria to the nucleus is crucial in sensing homeostasis and translating extracellular signals into altered gene expression (6). Mitochondria-directed changes in nuclear gene function (17) are presumably related to a mitochondrion’s role in generating and regulating high energy molecules, such as ATP, acetyl-CoA, and alpha-ketoglutarate.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial Genomic Backgrounds Affect Nuclear DNA Methylation and Gene Expression

et al. 2017

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Mitochondrial DNA (mtDNA) mutations and polymorphisms contribute to many complex diseases, including cancer. Using a unique mouse model that contains nDNA from one mouse strain and homoplasmic mitochondrial haplotypes from different mouse strain(s) - designated Mitochondrial Nuclear Exchange (MNX) – we showed that mtDNA could alter mammary tumor metastasis. Since retrograde and anterograde communication exist between the nuclear and mitochondrial genomes, we hypothesized that there are differential mtDNA-driven changes in nuclear (n)DNA expression and DNA methylation. Genome-wide nDNA methylation and gene expression were measured in harvested brain tissue from paired wild-type and MNX mice. Selective differential DNA methylation and gene expression were observed between strains having identical nDNA, but different mtDNA. These observations provide insights into how mtDNA could be altering epigenetic regulation and thereby contribute to the pathogenesis of metastasis.

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Mitochondrial Protein Synthesis Adapts to Influx of Nuclear-Encoded Protein

Cited by 179 publications

References 62 publications

MITRAC15/COA1 promotes mitochondrial translation in a ND2 ribosome–nascent chain complex

MITRAC15/COA1 promotes mitochondrial translation in a ND2 ribosome–nascent chain complex

Human mitochondrial cytochrome c oxidase assembly factor COX18 acts transiently as a membrane insertase within the subunit 2 maturation module

Mitochondrial Genomic Backgrounds Affect Nuclear DNA Methylation and Gene Expression

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