bims-tricox 2023-09-17 papers

Issue of 2023–09–17
five papers selected by
Yash Verma, University of Zurich

IUBMB Life. 2023 Sep 15.

Early steps in the biogenesis of mitochondrially encoded oxidative phosphorylation subunits.

Sung-Jun Jung, Sagar Sridhara, Martin Ott.

The complexes mediating oxidative phosphorylation (OXPHOS) in the inner mitochondrial membrane consist of proteins encoded in the nuclear or the mitochondrial DNA. The mitochondrially encoded membrane proteins (mito-MPs) represent the catalytic core of these complexes and follow complicated pathways for biogenesis. Owing to their overall hydrophobicity, mito-MPs are co-translationally inserted into the inner membrane by the Oxa1 insertase. After insertion, OXPHOS biogenesis factors mediate the assembly of mito-MPs into complexes and participate in the regulation of mitochondrial translation, while protein quality control factors recognize and degrade faulty or excess proteins. This review summarizes the current understanding of these early steps occurring during the assembly of mito-MPs by concentrating on results obtained in the model organism baker's yeast.

Keywords: eukaryotic gene expression; mitochondria; protein folding; protein synthesis

DOI: https://doi.org/10.1002/iub.2784

bioRxiv. 2023 Sep 02. pii: 2023.09.02.556006. [Epub ahead of print]

Cryo-EM studies of the interplay between uS2 ribosomal protein and leaderless mRNA during bacterial translation initiation.

Francisco J Acosta-Reyes, Sayan Bhattacharjee, Max Gottesman, Joachim Frank.

E. coli ribosomes lacking ribosomal protein uS2 translate leaderless transcripts more efficiently than wild-type ribosomes 1 Without the Shine-Dalgarno sequence, translation initiation occurs on the mutant 70S complex rather than the 30S initiation complex. The ribosome uses the initiation codon (AUG) and the first bases of the transcript, including a downstream box (DB) sequence, as recognition signals. We used cryo-EM to solve the structures of the uS2-deficient 70S ribosome and the wild-type 70S complex bound to leaderless mRNA (lmRNA) in the presence of fmet-tRNA fMet . Importantly, the uS2-deficient 70S ribosome also lacks protein bS21. The anti-Shine-Dalgarno (aSD) region is supported by bS21, and the absence of the latter causes the aSD to divert from the normal mRNA exit pathway. We identified a π-stacking interaction between a monitor base (1493A) and the first base (A +4 ) of lmRNA following the AUG and potentially stabilizing it. Coulomb charge flow and swapping along with peristalsis-like dynamics within the mRNA entry channel are likely to facilitate the propagation of lmRNA through the ribosome.

DOI: https://doi.org/10.1101/2023.09.02.556006

Nat Struct Mol Biol. 2023 Sep 11.

Molecular pathway of mitochondrial preprotein import through the TOM-TIM23 supercomplex.

Xueyin Zhou, Yuqi Yang, Guopeng Wang, Shanshan Wang, Dongjie Sun, Xiaomin Ou, Yuke Lian, Long Li.

Over half of mitochondrial proteins are imported from the cytosol via the pre-sequence pathway, controlled by the TOM complex in the outer membrane and the TIM23 complex in the inner membrane. The mechanisms through which proteins are translocated via the TOM and TIM23 complexes remain unclear. Here we report the assembly of the active TOM-TIM23 supercomplex of Saccharomyces cerevisiae with translocating polypeptide substrates. Electron cryo-microscopy analyses reveal that the polypeptide substrates pass the TOM complex through the center of a Tom40 subunit, interacting with a glutamine-rich region. Structural and biochemical analyses show that the TIM23 complex contains a heterotrimer of the subunits Tim23, Tim17 and Mgr2. The polypeptide substrates are shielded from lipids by Mgr2 and Tim17, which creates a translocation pathway characterized by a negatively charged entrance and a central hydrophobic region. These findings reveal an unexpected pre-sequence pathway through the TOM-TIM23 supercomplex spanning the double membranes of mitochondria.

DOI: https://doi.org/10.1038/s41594-023-01103-7

BMC Biol. 2023 09 12. 21(1): 193

Prefoldin 2 contributes to mitochondrial morphology and function.

Ismail Tahmaz, Somayeh Shahmoradi Ghahe, Monika Stasiak, Kamila P Liput, Katarzyna Jonak, Ulrike Topf.

BACKGROUND: Prefoldin is an evolutionarily conserved co-chaperone of the tailless complex polypeptide 1 ring complex (TRiC)/chaperonin containing tailless complex 1 (CCT). The prefoldin complex consists of six subunits that are known to transfer newly produced cytoskeletal proteins to TRiC/CCT for folding polypeptides. Prefoldin function was recently linked to the maintenance of protein homeostasis, suggesting a more general function of the co-chaperone during cellular stress conditions. Prefoldin acts in an adenosine triphosphate (ATP)-independent manner, making it a suitable candidate to operate during stress conditions, such as mitochondrial dysfunction. Mitochondrial function depends on the production of mitochondrial proteins in the cytosol. Mechanisms that sustain cytosolic protein homeostasis are vital for the quality control of proteins destined for the organelle and such mechanisms among others include chaperones.
RESULTS: We analyzed consequences of the loss of prefoldin subunits on the cell proliferation and survival of Saccharomyces cerevisiae upon exposure to various cellular stress conditions. We found that prefoldin subunits support cell growth under heat stress. Moreover, prefoldin facilitates the growth of cells under respiratory growth conditions. We showed that mitochondrial morphology and abundance of some respiratory chain complexes was supported by the prefoldin 2 (Pfd2/Gim4) subunit. We also found that Pfd2 interacts with Tom70, a receptor of mitochondrial precursor proteins that are targeted into mitochondria.
CONCLUSIONS: Our findings link the cytosolic prefoldin complex to mitochondrial function. Loss of the prefoldin complex subunit Pfd2 results in adaptive cellular responses on the proteome level under physiological conditions suggesting a continuous need of Pfd2 for maintenance of cellular homeostasis. Within this framework, Pfd2 might support mitochondrial function directly as part of the cytosolic quality control system of mitochondrial proteins or indirectly as a component of the protein homeostasis network.

Keywords: Chaperone; Mitochondria; Pfd2/Gim4; Prefoldin; Proteostasis; Tom70

DOI: https://doi.org/10.1186/s12915-023-01695-y

Mol Cell. 2023 Sep 07. pii: S1097-2765(23)00656-1. [Epub ahead of print]

Mitochondrial degradation: Mitophagy and beyond.

Louise Uoselis, Thanh Ngoc Nguyen, Michael Lazarou.

Mitochondria are central hubs of cellular metabolism that also play key roles in signaling and disease. It is therefore fundamentally important that mitochondrial quality and activity are tightly regulated. Mitochondrial degradation pathways contribute to quality control of mitochondrial networks and can also regulate the metabolic profile of mitochondria to ensure cellular homeostasis. Here, we cover the many and varied ways in which cells degrade or remove their unwanted mitochondria, ranging from mitophagy to mitochondrial extrusion. The molecular signals driving these varied pathways are discussed, including the cellular and physiological contexts under which the different degradation pathways are engaged.

Keywords: MDV; PINK1; Parkin; degradation; mitochondria; mitochondrial quality control; mitophagy; proteasome; selective autophagy; ubiquitin

DOI: https://doi.org/10.1016/j.molcel.2023.08.021