bims-mitpro 2023-09-24 papers

Issue of 2023‒09‒24
five papers selected by
Andreas Kohler

Sci Adv. 2023 Sep 22. 9(38): eadh8228

Temporal landscape of mitochondrial proteostasis governed by the UPRmt.

Louise Uoselis, Runa Lindblom, Wai Kit Lam, Catharina J Küng, Marvin Skulsuppaisarn, Grace Khuu, Thanh N Nguyen, Danielle L Rudler, Aleksandra Filipovska, Ralf B Schittenhelm, Michael Lazarou.

Breakdown of mitochondrial proteostasis activates quality control pathways including the mitochondrial unfolded protein response (UPRmt) and PINK1/Parkin mitophagy. However, beyond the up-regulation of chaperones and proteases, we have a limited understanding of how the UPRmt remodels and restores damaged mitochondrial proteomes. Here, we have developed a functional proteomics framework, termed MitoPQ (Mitochondrial Proteostasis Quantification), to dissect the UPRmt's role in maintaining proteostasis during stress. We find essential roles for the UPRmt in both protecting and repairing proteostasis, with oxidative phosphorylation metabolism being a central target of the UPRmt. Transcriptome analyses together with MitoPQ reveal that UPRmt transcription factors drive independent signaling arms that act in concert to maintain proteostasis. Unidirectional interplay between the UPRmt and PINK1/Parkin mitophagy was found to promote oxidative phosphorylation recovery when the UPRmt failed. Collectively, this study defines the network of proteostasis mediated by the UPRmt and highlights the value of functional proteomics in decoding stressed proteomes.

DOI: https://doi.org/10.1126/sciadv.adh8228

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

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

J Cell Sci. 2023 Sep 15. pii: jcs241125. [Epub ahead of print]136(18):

Chloroplast protein translocation pathways and ubiquitin-dependent regulation at a glance.

Sreedhar Nellaepalli, Anne Sophie Lau, R Paul Jarvis.

Chloroplasts conduct photosynthesis and numerous metabolic and signalling processes that enable plant growth and development. Most of the ∼3000 proteins in chloroplasts are nucleus encoded and must be imported from the cytosol. Thus, the protein import machinery of the organelle (the TOC-TIC apparatus) is of fundamental importance for chloroplast biogenesis and operation. Cytosolic factors target chloroplast precursor proteins to the TOC-TIC apparatus, which drives protein import across the envelope membranes into the organelle, before various internal systems mediate downstream routing to different suborganellar compartments. The protein import system is proteolytically regulated by the ubiquitin-proteasome system (UPS), enabling centralized control over the organellar proteome. In addition, the UPS targets a range of chloroplast proteins directly. In this Cell Science at a Glance article and the accompanying poster, we present mechanistic details of these different chloroplast protein targeting and translocation events, and of the UPS systems that regulate chloroplast proteins.

Keywords: Chloroplast; Plastid; Protein degradation; Protein import; Protein translocation; Ubiquitin

DOI: https://doi.org/10.1242/jcs.241125

Mitochondrion. 2023 Sep 20. pii: S1567-7249(23)00083-1. [Epub ahead of print]

The Constraints of Allotopic Expression.

Felipe Nieto-Panqueva, Diana Rubalcava-Gracia, Patrice P Hamel, Diego González-Halphen.

Allotopic expression is the functional transfer of an organellar gene to the nucleus, followed by synthesis of the gene product in the cytosol and import into the appropriate organellar sub compartment. Here, we focus on mitochondrial genes encoding OXPHOS subunits that were naturally transferred to the nucleus, and critically review experimental evidence that claim their allotopic expression. We emphasize aspects that may have been overlooked before, i.e., when modifying a mitochondrial gene for allotopic expression ━besides adapting the codon usage and including sequences encoding mitochondrial targeting signals━ three additional constraints should be considered: i) the average apparent free energy of membrane insertion (μΔGapp) of the transmembrane stretches (TMS) in proteins earmarked for the inner mitochondrial membrane, ii) the final, functional topology attained by each membrane-bound OXPHOS subunit; and iii) the defined mechanism by which the protein translocator TIM23 sorts cytosol-synthesized precursors. The mechanistic constraints imposed by TIM23 dictate the operation of two pathways through which alpha-helices in TMS are sorted, that eventually determine the final topology of membrane proteins. We used the biological hydrophobicity scale to assign an average apparent free energy of membrane insertion (μΔGapp) and a "traffic light" color code to all TMS of OXPHOS membrane proteins, thereby predicting which are more likely to be internalized into mitochondria if allotopically produced. We propose that the design of proteins for allotopic expression must make allowance for μΔGapp maximization of highly hydrophobic TMS in polypeptides whose corresponding genes have not been transferred to the nucleus in some organisms.

Keywords: TIM23; allotopic expression; apparent free energy of membrane insertion; membrane embedded proteins; mitochondrial complexes; oxidative phosphorylation; protein import; transmembrane stretches

DOI: https://doi.org/10.1016/j.mito.2023.09.004