bims-tricox 2023-09-24 papers

Issue of 2023–09–24
five papers selected by
Yash Verma, University of Zurich

FEBS J. 2023 Sep 18.

Yeast mitochondria can process de novo designed β-barrel proteins.

Anasuya Moitra, Vitasta Tiku, Doron Rapaport.

Mitochondrial outer membrane β-barrel proteins are encoded in the nucleus, translated in the cytosol, and then targeted to and imported into the respective organelles. Detailed studies have uncovered the mechanisms involved in the import of these proteins and identified the targeting signals and the cytosolic factors that govern their proper biogenesis. Recently, de novo designed eight stranded β-barrel proteins (Tmb2.3 and Tmb2.17) were shown to fold and assemble into lipid membranes. To better understand the general aspects of the biogenesis of β-barrel proteins, we investigated the fate of these artificial proteins upon their expression in yeast cells. We demonstrate that although these proteins are de novo designed and are not related to bona fide mitochondrial β-barrel proteins, they were targeted to mitochondria and integrated into the organelle outer membrane. We further studied whether this integration requires components of the yeast mitochondrial import machinery like Tom20, Tom70, Tob55/Sam50, and Mas37/Sam37. Whereas it seems that none of the import receptors was required for the biogenesis of the artificial β-barrel proteins, we observed a strong dependency on the TOB/SAM complex. Collectively, our findings demonstrate that the mitochondrial outer membrane is the preferential location in yeast cells for any membrane embedded β-barrel protein.

Keywords: TOB/SAM complex; de novo designed proteins; mitochondria; outer membrane; β-barrel proteins

DOI: https://doi.org/10.1111/febs.16950

Nat Genet. 2023 Sep 18.

Molecular basis for maternal inheritance of human mitochondrial DNA.

William Lee, Angelica Zamudio-Ochoa, Gina Buchel, Petar Podlesniy, Nuria Marti Gutierrez, Margalida Puigròs, Anna Calderon, Hsin-Yao Tang, Li Li, Aleksei Mikhalchenko, Amy Koski, Ramon Trullas, Shoukhrat Mitalipov, Dmitry Temiakov.

Uniparental inheritance of mitochondrial DNA (mtDNA) is an evolutionary trait found in nearly all eukaryotes. In many species, including humans, the sperm mitochondria are introduced to the oocyte during fertilization1,2. The mechanisms hypothesized to prevent paternal mtDNA transmission include ubiquitination of the sperm mitochondria and mitophagy3,4. However, the causative mechanisms of paternal mtDNA elimination have not been defined5,6. We found that mitochondria in human spermatozoa are devoid of intact mtDNA and lack mitochondrial transcription factor A (TFAM)-the major nucleoid protein required to protect, maintain and transcribe mtDNA. During spermatogenesis, sperm cells express an isoform of TFAM, which retains the mitochondrial presequence, ordinarily removed upon mitochondrial import. Phosphorylation of this presequence prevents mitochondrial import and directs TFAM to the spermatozoon nucleus. TFAM relocalization from the mitochondria of spermatogonia to the spermatozoa nucleus directly correlates with the elimination of mtDNA, thereby explaining maternal inheritance in this species.

DOI: https://doi.org/10.1038/s41588-023-01505-9

Mol Cell. 2023 Sep 21. pii: S1097-2765(23)00691-3. [Epub ahead of print]83(18): 3232-3233

Fellowship of two rings: Unprecedented insights into the structure of the yeast nuclear pore complex.

Anita H Corbett, Milo B Fasken.

Akey et al.1 use complementary experimental approaches and AI-based structure prediction to reveal new details of the structure of the yeast nuclear pore complex, providing key insights into evolution, assembly, and nucleocytoplasmic transport mechanisms.

DOI: https://doi.org/10.1016/j.molcel.2023.08.028

IUBMB Life. 2023 Sep 20.

Mitochondrial protein and organelle quality control-Lessons from budding yeast.

Emily Jie-Ning Yang, Pin-Chao Liao, Liza Pon.

Mitochondria are essential for normal cellular function and have emerged as key aging determinants. Indeed, defects in mitochondrial function have been linked to cardiovascular, skeletal muscle and neurodegenerative diseases, premature aging, and age-linked diseases. Here, we describe mechanisms for mitochondrial protein and organelle quality control. These surveillance mechanisms mediate repair or degradation of damaged or mistargeted mitochondrial proteins, segregate mitochondria based on their functional state during asymmetric cell division, and modulate cellular fitness, the response to stress, and lifespan control in yeast and other eukaryotes.

Keywords: ageing; mitochondria; mitochondrial reactive oxygen species; oxidative stress; reactive oxygen species

DOI: https://doi.org/10.1002/iub.2783

Mol Cell. 2023 Sep 21. pii: S1097-2765(23)00661-5. [Epub ahead of print]83(18): 3283-3302.e5

Implications of a multiscale structure of the yeast nuclear pore complex.

Christopher W Akey, Ignacia Echeverria, Christna Ouch, Ilona Nudelman, Yi Shi, Junjie Wang, Brian T Chait, Andrej Sali, Javier Fernandez-Martinez, Michael P Rout.

Nuclear pore complexes (NPCs) direct the nucleocytoplasmic transport of macromolecules. Here, we provide a composite multiscale structure of the yeast NPC, based on improved 3D density maps from cryogenic electron microscopy and AlphaFold2 models. Key features of the inner and outer rings were integrated into a comprehensive model. We resolved flexible connectors that tie together the core scaffold, along with equatorial transmembrane complexes and a lumenal ring that anchor this channel within the pore membrane. The organization of the nuclear double outer ring reveals an architecture that may be shared with ancestral NPCs. Additional connections between the core scaffold and the central transporter suggest that under certain conditions, a degree of local organization is present at the periphery of the transport machinery. These connectors may couple conformational changes in the scaffold to the central transporter to modulate transport. Collectively, this analysis provides insights into assembly, transport, and NPC evolution.

Keywords: AlphaFold2 modeling; FG repeats; computed structure models; cryo-EM; cryogenic electron microscopy; nuclear pore complex; nucleocytoplasmic transport; single-particle analysis

DOI: https://doi.org/10.1016/j.molcel.2023.08.025