bims-tricox 2023-06-11 papers

Issue of 2023–06–11
three papers selected by
Yash Verma, University of Zurich

FEBS Lett. 2023 Jun 05.

Defective mitochondrial import as a challenge for cellular protein homeostasis.

Klaudia K Maruszczak, Selvaraj Ayyamperumal, Agnieszka Chacinska.

Mitochondria are organelles indispensable for the correct functioning of eukaryotic cells. Their significance for cellular homeostasis is manifested by the existence of complex quality control pathways that monitor organellar fitness. Mitochondrial biogenesis relies on the efficient import of mitochondrial precursor proteins, a large majority of which are encoded by nuclear DNA and synthesized in the cytosol. This creates a demand for highly specialized import routes that comprise cytosolic factors and organellar translocases. The passage of newly encoded mitochondrial precursor proteins through the cytosol to the translocase of the outer mitochondrial membrane (TOM) is under tight surveillance. As a result of mitochondrial import defects, mitochondrial precursor proteins accumulate in the cytosol or clog the TOM complex, which in turn stimulates cellular stress responses to minimize the consequences of these challenges. These responses are critical for maintaining protein homeostasis under conditions of mitochondrial stress. The present review summarizes recent advances in the field of mitochondrial protein import quality control and discusses the role of this quality control within the network of cellular mechanisms that maintain the cellular homeostasis of proteins.

Keywords: cellular stress responses; mitochondria; mitochondrial dysfunction; mitochondrial quality control; protein aggregates; protein homeostasis

DOI: https://doi.org/10.1002/1873-3468.14677

Nat Struct Mol Biol. 2023 Jun 08.

Structure of nascent 5S RNPs at the crossroad between ribosome assembly and MDM2-p53 pathways.

Nestor Miguel Castillo Duque de Estrada, Matthias Thoms, Dirk Flemming, Henrik M Hammaren, Robert Buschauer, Michael Ameismeier, Jochen Baßler, Martin Beck, Roland Beckmann, Ed Hurt.

The 5S ribonucleoprotein (RNP) is assembled from its three components (5S rRNA, Rpl5/uL18 and Rpl11/uL5) before being incorporated into the pre-60S subunit. However, when ribosome synthesis is disturbed, a free 5S RNP can enter the MDM2-p53 pathway to regulate cell cycle and apoptotic signaling. Here we reconstitute and determine the cryo-electron microscopy structure of the conserved hexameric 5S RNP with fungal or human factors. This reveals how the nascent 5S rRNA associates with the initial nuclear import complex Syo1-uL18-uL5 and, upon further recruitment of the nucleolar factors Rpf2 and Rrs1, develops into the 5S RNP precursor that can assemble into the pre-ribosome. In addition, we elucidate the structure of another 5S RNP intermediate, carrying the human ubiquitin ligase Mdm2, which unravels how this enzyme can be sequestered from its target substrate p53. Our data provide molecular insight into how the 5S RNP can mediate between ribosome biogenesis and cell proliferation.

DOI: https://doi.org/10.1038/s41594-023-01006-7

EMBO Rep. 2023 Jun 05. e56430

Human Tim8a, Tim8b and Tim13 are auxiliary assembly factors of mature Complex IV.

Alexander J Anderson, Jordan J Crameri, Ching-Seng Ang, Tess R Malcolm, Yilin Kang, Megan J Baker, Catherine S Palmer, Alice J Sharpe, Luke E Formosa, Katherine Ganio, Michael J Baker, Christopher A McDevitt, Michael T Ryan, Megan J Maher, Diana Stojanovski.

Human Tim8a and Tim8b are paralogous intermembrane space proteins of the small TIM chaperone family. Yeast small TIMs function in the trafficking of proteins to the outer and inner mitochondrial membranes. This putative import function for hTim8a and hTim8b has been challenged in human models, but their precise molecular function(s) remains undefined. Likewise, the necessity for human cells to encode two Tim8 proteins and whether any potential redundancy exists is unclear. We demonstrate that hTim8a and hTim8b function in the assembly of cytochrome c oxidase (Complex IV). Using affinity enrichment mass spectrometry, we define the interaction network of hTim8a, hTim8b and hTim13, identifying subunits and assembly factors of the Complex IV COX2 module. hTim8-deficient cells have a COX2 and COX3 module defect and exhibit an accumulation of the Complex IV S2 subcomplex. These data suggest that hTim8a and hTim8b function in assembly of Complex IV via interactions with intermediate-assembly subcomplexes. We propose that hTim8-hTim13 complexes are auxiliary assembly factors involved in the formation of the Complex IV S3 subcomplex during assembly of mature Complex IV.

Keywords: Complex IV; mitochondria; protein assembly; protein trafficking; small TIMs

DOI: https://doi.org/10.15252/embr.202256430