Inventory control: cytochrome c oxidase assembly regulates mitochondrial translation

Mick, David U.; Fox, Thomas D.; Rehling, Peter

doi:10.1038/nrm3029

Cited by 190 publications

(196 citation statements)

References 67 publications

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“…6A, B). Diminished levels of Cox1 synthesis are characteristic for strains with defects in the assembly of cytochrome c oxidase (5,21,37,44,45). The levels of Cox1 were not increased in the presence of DTT, indicating that DTT did not suppress the assembly defect in these strains (Fig.…”

Section: Mutants Lacking Cmc1 or Coa4 Show Reduced Levels Of Cytochromentioning

confidence: 91%

“…In particular, assembly intermediates of Cox1 containing heme but no copper killed hydrogen peroxide-treated cytochrome c oxidase mutants on glucose medium. This cytotoxic potential might explain why mitochondrial Cox1 synthesis is under tight feedback control, which prevents the accumulation of assembly intermediates (5,21,37,44,45). At this stage it is not entirely clear where the ROS are produced.…”

Section: Discussionmentioning

confidence: 99%

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Inaccurately Assembled CytochromecOxidase Can Lead to Oxidative Stress-Induced Growth Arrest

Bode

Longen

Morgan

et al. 2013

Antioxidants & Redox Signaling

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Aims: To identify yeast mutants that show a strong redox dependence of the ability to respire, we systematically screened a yeast deletion library for mutants that require the presence of reductants for growth on nonfermentable carbon sources. Results: Respirative growth of 44 yeast mutants was significantly improved by the addition of dithiothreitol or glutathione. Two mutants that were strongly stimulated by reductants lacked the proteins Cmc1 and Coa4. Both proteins belong to the family of ''twin Cx 9 C'' proteins present in the intermembrane space of mitochondria. Deletion of CMC1 or COA4 leads to assembly defects of cytochrome c oxidase, in particular to the lack of Cox1 and rapid degradation of Cox2 and Cox3. Interestingly, the presence of the reductants does not suppress these assembly defects and the levels of cytochrome c oxidase remain reduced. Reductants and antioxidants such as ascorbic acid rather counteract the effects of hydrogen peroxide that is produced from partially assembled cytochrome c oxidase intermediates. Innovation: Here we show that oxidative stress generated by the accumulation of partially assembled respiratory chain complexes prevents growth on carbon sources that force cells to respire. Conclusion: Defects in the assembly of cytochrome c oxidase can lead to increased production of hydrogen peroxide, which is sensed in cells and blocks their proliferation. We propose that this redox-regulated feedback regulation specifically slows down the propagation of cells carrying respiratory chain mutations in order to select for cells of high mitochondrial fitness. Antioxid. Redox Signal. 18, 1597-1612.

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Section: Mutants Lacking Cmc1 or Coa4 Show Reduced Levels Of Cytochromentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Inaccurately Assembled CytochromecOxidase Can Lead to Oxidative Stress-Induced Growth Arrest

Bode

Longen

Morgan

et al. 2013

Antioxidants & Redox Signaling

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“…To assess whether the Pet117-Cox15 interaction is direct or instead mediated by other proteins, such as the multiprotein Cox1-containing CcO assembly intermediates, co-IP experiments were performed in the absence of the Mss51 and Shy1 assembly factors, which were chosen because the mss51⌬ and shy1⌬ deletions block Cox1 synthesis/assembly at early and late stages, respectively (2,7,12). The Cox15-Pet117 interaction was drastically attenuated in mitochondria from mss51⌬ cells (Fig.…”

Section: Pet117 Promotes Cco Assembly By Stabilizing Cox15mentioning

confidence: 99%

“…Heme a delivery to maturing Cox1 also depends on two additional proteins, Shy1/SURF1 and Coa2 (3,7). The formation of the heme a and heme a 3 centers appears to occur within the Shy1-containing Cox1 assembly intermediate, and Shy1 appears to chaperone maturation of the heme a 3 site rather than serve as a direct heme a donor to newly synthesized Cox1 (12).…”

mentioning

confidence: 99%

“…After its translation by a mitochondrial ribosome and insertion into the mitochondrial inner membrane (IM), Cox1 undergoes sequential maturation aided by multiple assembly factors and receives its cofactors (2,3,7). Before being joined by the other core CcO subunits, Cox1 can be found in at least three distinct assembly intermediate complexes, which can be identified by the characteristic presence of the assembly factors Mss51, Coa1, and Shy1, respectively (Fig.…”

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confidence: 99%

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The Assembly Factor Pet117 Couples Heme a Synthase Activity to Cytochrome Oxidase Assembly

Taylor

Swenson

Harris

et al. 2017

Journal of Biological Chemistry

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Edited by Ruma BanerjeeHeme a is an essential metalloporphyrin cofactor of the mitochondrial respiratory enzyme cytochrome c oxidase (CcO). Its synthesis from heme b requires several enzymes, including the evolutionarily conserved heme a synthase (Cox15). Oligomerization of Cox15 appears to be important for the process of heme a biosynthesis and transfer to maturing CcO. However, the details of this process remain elusive, and the roles of any additional CcO assembly factors that may be involved remain unclear. Here we report the systematic analysis of one such uncharacterized assembly factor, Pet117, and demonstrate in Saccharomyces cerevisiae that this evolutionarily conserved protein is necessary for Cox15 oligomerization and function. Pet117 is shown to reside in the mitochondrial matrix, where it is associated with the inner membrane. Pet117 functions at the later maturation stages of the core CcO subunit Cox1 that precede Cox1 hemylation. Pet117 also physically interacts with Cox15 and specifically mediates the stability of Cox15 oligomeric complexes. This Cox15-Pet117 interaction observed by co-immunoprecipitation persists in the absence of heme a synthase activity, is dependent upon Cox1 synthesis and early maturation steps, and is further dependent upon the presence of the matrix-exposed, unstructured linker region of Cox15 needed for Cox15 oligomerization, suggesting that this region mediates the interaction or that the interaction is lost when Cox15 is unable to oligomerize. Based on these findings, it was concluded that Pet117 mediates coupling of heme a synthesis to the CcO assembly process in eukaryotes.

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The N‐terminal region of yeast mitoribosomal Mrp7/bL27m protein serves to optimize translation of nascent chains competent for OXPHOS complex assembly

2023

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The extreme N-terminal residues of the mitochondrial ribosomal bL27m proteins reside within the ribosomal peptidyl transferase center (PTC) and are conserved from their bacterial ancestors. Mutation or truncation of the N-terminal region of the yeast Mrp7/bL27m protein did not inhibit protein synthesis but significantly impacted the efficacy of the mitochondrial translational process with respect to yielding proteins competent to assemble into functional oxidative phosphorylation enzymes. The requirement for the N-terminal residues of Mrp7/bL27m to support normal mitotranslation was more apparent under respiratory growth. We demonstrate that the N-terminal region of Mrp7/bL27m impacts the environment of the PTC and speculate the bL27m proteins serve to fine-tune and optimize mitoribosomal activity with respect to the downstream fate of the nascent chain.

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Inventory control: cytochrome c oxidase assembly regulates mitochondrial translation

Cited by 190 publications

References 67 publications

Inaccurately Assembled CytochromecOxidase Can Lead to Oxidative Stress-Induced Growth Arrest

Inaccurately Assembled CytochromecOxidase Can Lead to Oxidative Stress-Induced Growth Arrest

The Assembly Factor Pet117 Couples Heme a Synthase Activity to Cytochrome Oxidase Assembly

The N‐terminal region of yeast mitoribosomal Mrp7/bL27m protein serves to optimize translation of nascent chains competent for OXPHOS complex assembly

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