bims-tricox 2024-08-04 papers

Issue of 2024–08–04
six papers selected by
Yash Verma, University of Zurich

Biol Chem. 2024 Aug 02.

The TOM complex from an evolutionary perspective and the functions of TOMM70.

In humans, up to 1,500 mitochondrial precursor proteins are synthesized at cytosolic ribosomes and must be imported into the organelle. This is not only essential for mitochondrial but also for many cytosolic functions. The majority of mitochondrial precursor proteins are imported over the translocase of the outer membrane (TOM). In recent years, high-resolution structure analyses from different organisms shed light on the composition and arrangement of the TOM complex. Although significant similarities have been found, differences were also observed, which have been favored during evolution and could reflect the manifold functions of TOM with cellular signaling and its response to altered metabolic situations. A key component within these regulatory mechanisms is TOMM70, which is involved in protein import, forms contacts to the ER and the nucleus, but is also involved in cellular defense mechanisms during infections.

Keywords: TOM complex; mitochondria; mitochondrial import

DOI: https://doi.org/10.1515/hsz-2024-0043

bioRxiv. 2024 Jul 19. pii: 2024.07.17.604013. [Epub ahead of print]

Cytoplasmic ribosomes on mitochondria alter the local membrane environment for protein import.

Ya-Ting Chang, Benjamin A Barad, Hamidreza Rahmani, Brian M Zid, Danielle A Grotjahn.

Most of the mitochondria proteome is nuclear-encoded, synthesized by cytoplasmic ribosomes, and targeted to mitochondria post-translationally. However, a subset of mitochondrial-targeted proteins is imported co-translationally, although the molecular mechanisms governing this process remain unclear. We employ cellular cryo-electron tomography to visualize interactions between cytoplasmic ribosomes and mitochondria in Saccharomyces cerevisiae. We use surface morphometrics tools to identify a subset of ribosomes optimally oriented on mitochondrial membranes for protein import. This allows us to establish the first subtomogram average structure of a cytoplasmic ribosome on the surface of the mitochondria in the native cellular context, which showed three distinct connections with the outer mitochondrial membrane surrounding the peptide exit tunnel. Further, this analysis demonstrated that cytoplasmic ribosomes primed for mitochondrial protein import cluster on the outer mitochondrial membrane at sites of local constrictions of the outer and inner mitochondrial membrane. Overall, our study reveals the architecture and the spatial organization of cytoplasmic ribosomes at the mitochondrial surface, providing a native cellular context to define the mechanisms that mediate efficient mitochondrial co-translational protein import.

DOI: https://doi.org/10.1101/2024.07.17.604013

Trends Cell Biol. 2024 Jul 31. pii: S0962-8924(24)00145-4. [Epub ahead of print]

The ATP-driven extractor ATAD1/Msp1 proof-reads protein translocation into mitochondria.

Maria Bohnert, Christos Gatsogiannis, Johannes M Herrmann.

The accumulation of translocation intermediates in the mitochondrial import machinery threatens cellular fitness and is associated with cancer and neurodegeneration. A recent study by Weidberg and colleagues identifies ATAD1 as an ATP-driven extraction machine on the mitochondrial surface that pulls precursors into the cytosol to prevent clogging of mitochondrial import pores.

Keywords: AAA protein; cancer; integrated stress response (ISR); mitochondria; protein import; quality control

DOI: https://doi.org/10.1016/j.tcb.2024.07.007

PNAS Nexus. 2024 Jul;3(7): pgae269

Structure of the intact Tom20 receptor in the human translocase of the outer membrane complex.

Jiayue Su, Xuyang Tian, Ziyi Wang, Jiawen Yang, Shan Sun, Sen-Fang Sui.

The translocase of the outer membrane (TOM) complex serves as the main gate for preproteins entering mitochondria and thus plays a pivotal role in sustaining mitochondrial stability. Precursor proteins, featuring amino-terminal targeting signals (presequences) or internal targeting signals, are recognized by the TOM complex receptors Tom20, Tom22, and Tom70, and then translocated into mitochondria through Tom40. By using chemical cross-linking to stabilize Tom20 in the TOM complex, this study unveils the structure of the human TOM holo complex, encompassing the intact Tom20 component, at a resolution of approximately 6 Å by cryo-electron microscopy. Our structure shows the TOM holo complex containing only one Tom20 subunit, which is located right at the center of the complex and stabilized by extensive interactions with Tom22, Tom40, and Tom6. Based on the structure, we proposed a possible translocation mode of TOM complex, by which different receptors could work simultaneously to ensure that the preproteins recognized by them are all efficiently translocated into the mitochondria.

Keywords: Tom20; cryo-electron microscopy; mitochondria; translocase of the outer membrane complex

DOI: https://doi.org/10.1093/pnasnexus/pgae269

Nucleic Acids Res. 2024 Aug 01. pii: gkae662. [Epub ahead of print]

LRPPRC and SLIRP synergize to maintain sufficient and orderly mammalian mitochondrial translation.

Diana Rubalcava-Gracia, Kristina Bubb, Fredrik Levander, Stephen P Burr, Amelie V August, Patrick F Chinnery, Camilla Koolmeister, Nils-Göran Larsson.

In mammals, the leucine-rich pentatricopeptide repeat protein (LRPPRC) and the stem-loop interacting RNA-binding protein (SLIRP) form a complex in the mitochondrial matrix that is required throughout the life cycle of most mitochondrial mRNAs. Although pathogenic mutations in the LRPPRC and SLIRP genes cause devastating human mitochondrial diseases, the in vivo function of the corresponding proteins is incompletely understood. We show here that loss of SLIRP in mice causes a decrease of complex I levels whereas other OXPHOS complexes are unaffected. We generated knock-in mice to study the in vivo interdependency of SLIRP and LRPPRC by mutating specific amino acids necessary for protein complex formation. When protein complex formation is disrupted, LRPPRC is partially degraded and SLIRP disappears. Livers from Lrpprc knock-in mice had impaired mitochondrial translation except for a marked increase in the synthesis of ATP8. Furthermore, the introduction of a heteroplasmic pathogenic mtDNA mutation (m.C5024T of the tRNAAla gene) into Slirp knockout mice causes an additive effect on mitochondrial translation leading to embryonic lethality and reduced growth of mouse embryonic fibroblasts. To summarize, we report that the LRPPRC/SLIRP protein complex is critical for maintaining normal complex I levels and that it also coordinates mitochondrial translation in a tissue-specific manner.

DOI: https://doi.org/10.1093/nar/gkae662

Front Cell Dev Biol. 2024 ;12 1414269

Ribosome heterogeneity in development and disease.

Yuen Gao, Hongbing Wang.

Traditionally viewed as a fixed and homogeneous machinery for protein synthesis, the ribosome is increasingly recognized for its heterogeneity, as indicated by emerging studies highlighting the functional relevance of specialized ribosomes. However, whether ribosome heterogeneity is merely an outcome limited to specific conditions or a pervasive cellular phenomenon remains unclear, and existing evidence on the extensive existence of ribosome heterogeneity is scant. Here, we leveraged existing proteomic data and employed ribosome ratio-omics (RibosomeR), which comprehensively analyzes ribosome protein stoichiometry across various biological samples exhibiting distinct functions, developmental stages, and pathological states. Using the 80S monosome proteomic data, RibosomeR analysis unveils significant ribosome heterogeneity across different tissues, including fat, spleen, liver, kidney, heart, and skeletal muscles. Furthermore, examination of testes at various stages of spermatogenesis reveals distinct RibosomeR signatures during tissue development. Analysis of the whole cell proteomic data finds that RibosomeR undergoes dynamic changes during in vitro neuronal maturation, indicating functional associations with specific molecular aspects of neurodevelopment. In pathological contexts, RibosomeR signatures in gastric tumors demonstrate functional links to pathways associated with tumorigenesis. Additionally, dynamic alterations in RibosomeR are observed in macrophages following immune challenges. Collectively, our investigation across a diverse array of biological samples underscores the presence of ribosome heterogeneity, while previous studies observed functional aspects of ribosome specialization, in cellular function, development, and disease. The RibosomeR barcode serves as a valuable tool for elucidating these complexities.

Keywords: bioinformatics; cancer; development; macrophage; ribosome heterogeneity; stoichiometry

DOI: https://doi.org/10.3389/fcell.2024.1414269