bims-tricox 2023-06-04 papers

Issue of 2023‒06‒04
four papers selected by
Yash Verma
University of Zurich

FEBS Lett. 2023 May 29.

Cytochrome c oxidase biogenesis - from translation to early assembly of the core subunit COX1.

Sven Dennerlein, Peter Rehling, Ricarda Richter-Dennerlein.

Mitochondria are the powerhouses of the cell as they produce the majority of ATP with their oxidative phosphorylation (OXPHOS) machinery. The OXPHOS system is composed of the F1 Fo ATP synthase and four mitochondrial respiratory chain complexes, the terminal enzyme of which is the cytochrome c oxidase (complex IV) that transfers electrons to oxygen, generating water. Complex IV comprises of 14 structural subunits of dual genetic origin: while the three core subunits are mitochondrial encoded, the remaining constituents are encoded by the nuclear genome. Hence, the assembly of complex IV requires the coordination of two spatially separated gene expression machinery. Recent efforts elucidated an increasing number of proteins involved in mitochondrial gene expression, which are linked to complex IV assembly. Additionally, several COX1 biogenesis factors have been intensively biochemically investigated and an increasing number of structural snapshots shed light on the organization of macromolecular complexes such as the mitoribosome or the cytochrome c oxidase. Here, we focus on COX1 translation regulation and highlight the advanced understanding of early steps during COX1 assembly and its link to mitochondrial translation regulation.

Keywords: COX1; OXPHOS; complex IV; cytochrome c oxidase; mitochondria

DOI: https://doi.org/10.1002/1873-3468.14671

Nature. 2023 May 31.

Nuclear export of pre-60S particles through the nuclear pore complex.

Zongqiang Li, Shuaijiabin Chen, Liang Zhao, Guoqiang Huang, Huiqin Xu, Xiaoyun Yang, Peiyi Wang, Ning Gao, Sen-Fang Sui.

The nuclear pore complex (NPC) is the bidirectional gate that mediates the exchange of macromolecules or their assemblies between nucleus and cytoplasm1-3. The assembly intermediates of the ribosomal subunits, pre-60S and pre-40S particles, are among the largest cargoes of the NPC and the export of these gigantic ribonucleoproteins requires numerous export factors4,5. Here we report the cryo-electron microscopy structure of native pre-60S particles trapped in the channel of yeast NPCs. In addition to known assembly factors, multiple factors with export functions are also included in the structure. These factors in general bind to either the flexible regions or subunit interface of the pre-60S particle, and virtually form many anchor sites for NPC binding. Through interactions with phenylalanine-glycine (FG) repeats from various nucleoporins of NPC, these factors collectively facilitate the passage of the pre-60S particle through the central FG repeat network of the NPC. Moreover, in silico analysis of the axial and radial distribution of pre-60S particles within the NPC shows that a single NPC can take up to four pre-60S particles simultaneously, and pre-60S particles are enriched in the inner ring regions close to the wall of the NPC with the solvent-exposed surface facing the centre of the nuclear pore. Our data suggest a translocation model for the export of pre-60S particles through the NPC.

DOI: https://doi.org/10.1038/s41586-023-06128-y

Free Radic Biol Med. 2023 May 27. pii: S0891-5849(23)00446-X. [Epub ahead of print]

PET117 assembly factor stabilizes translation activator TACO1 thereby upregulates mitochondria-encoded cytochrome C oxidase 1 synthesis.

Qiong Sun, Le Shi, Shuaijun Li, Jialu Li, Ruifen Zhang, Xinghuai Huang, Yongping Shao, Zhihui Feng, Yunhua Peng, Zhiwei Yang, Jiankang Liu, Huadong Liu, Jiangang Long.

Cytochrome c oxidase, also known as complex IV, facilitates the transfer of electrons from cytochrome c to molecular oxygen, resulting in the production of ATP. The assembly of complex IV is a tightly regulated and intricate process that entails the coordinated synthesis and integration of subunits encoded by the mitochondria and nucleus into a functional complex. Accurate regulation of translation is crucial for maintaining proper mitochondrial function, and defects in this process can lead to a wide range of mitochondrial disorders and diseases. However, the mechanisms governing mRNA translation by mitoribosomes in mammals remain largely unknown. In this study, we elucidate the critical role of PET117, a chaperone protein involved in complex IV assembly, in the regulation of mitochondria-encoded cytochrome c oxidase 1 (COX1) protein synthesis in human cells. Depletion of PET117 reduced mitochondrial oxygen consumption rate and impaired mitochondrial function. PET117 was found to interact with and stabilize translational activator of COX1 (TACO1) and prevent its ubiquitination. TACO1 overexpression rescued the inhibitory effects on mitochondria caused by PET117 deficiency. These findings provide evidence for a novel PET117-TACO1 axis in the regulation of mitochondrial protein expression, and revealed a previously unknown role of PET117 in human cells.

Keywords: COX1; Mitochondrion; PET117; Protein stability; TACO1

DOI: https://doi.org/10.1016/j.freeradbiomed.2023.05.023

Cell Rep. 2023 May 31. pii: S2211-1247(23)00590-9. [Epub ahead of print]42(6): 112579

The E3 ubiquitin ligase FBXL6 controls the quality of newly synthesized mitochondrial ribosomal proteins.

Julie Lavie, Claude Lalou, Walid Mahfouf, Jean-William Dupuy, Aurélie Lacaule, Agata Ars Cywinska, Didier Lacombe, Anne-Marie Duchêne, Anne-Aurélie Raymond, Hamid Reza Rezvani, Richard Patryk Ngondo, Giovanni Bénard.

In mammals, about 99% of mitochondrial proteins are synthesized in the cytosol as precursors that are subsequently imported into the organelle. The mitochondrial health and functions rely on an accurate quality control of these imported proteins. Here, we show that the E3 ubiquitin ligase F box/leucine-rich-repeat protein 6 (FBXL6) regulates the quality of cytosolically translated mitochondrial proteins. Indeed, we found that FBXL6 substrates are newly synthesized mitochondrial ribosomal proteins. This E3 binds to chaperones involved in the folding and trafficking of newly synthesized peptide and to ribosomal-associated quality control proteins. Deletion of these interacting partners is sufficient to hamper interactions between FBXL6 and its substrate. Furthermore, we show that cells lacking FBXL6 fail to degrade specifically mistranslated mitochondrial ribosomal proteins. Finally, showing the role of FBXL6-dependent mechanism, FBXL6-knockout (KO) cells display mitochondrial ribosomal protein aggregations, altered mitochondrial metabolism, and inhibited cell cycle in oxidative conditions.

Keywords: CP: Cell biology; F box leucin-rich repeat E3 ubiquitin ligase; FBXL6; mitochondria; protein quality control; ribosomal proteins

DOI: https://doi.org/10.1016/j.celrep.2023.112579