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- Kohler, Andreas, Dr. rer. nat. 1988-, et al.
(författare)
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Early fate decision for mitochondrially encoded proteins by a molecular triage
- 2023
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Ingår i: Molecular Cell. - : Cell Press. - 1097-2765 .- 1097-4164. ; 83:19
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Tidskriftsartikel (refereegranskat)abstract
- Folding of newly synthesized proteins poses challenges for a functional proteome. Dedicated protein quality control (PQC) systems either promote the folding of nascent polypeptides at ribosomes or, if this fails, ensure their degradation. Although well studied for cytosolic protein biogenesis, it is not understood how these processes work for mitochondrially encoded proteins, key subunits of the oxidative phosphorylation (OXPHOS) system. Here, we identify dedicated hubs in proximity to mitoribosomal tunnel exits coordinating mitochondrial protein biogenesis and quality control. Conserved prohibitin (PHB)/m-AAA protease supercomplexes and the availability of assembly chaperones determine the fate of newly synthesized proteins by molecular triaging. The localization of these competing activities in the vicinity of the mitoribosomal tunnel exit allows for a prompt decision on whether newly synthesized proteins are fed into OXPHOS assembly or are degraded.
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| 3. |
- Keuenhof, Katharina, 1994, et al.
(författare)
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Nuclear envelope budding and its cellular functions
- 2023
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Ingår i: Nucleus. - : Informa UK Limited. - 1949-1034 .- 1949-1042. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- The nuclear pore complex (NPC) has long been assumed to be the sole route across the nuclear envelope, and under normal homeostatic conditions it is indeed the main mechanism of nucleo-cytoplasmic transport. However, it has also been known that e.g. herpesviruses cross the nuclear envelope utilizing a pathway entitled nuclear egress or envelopment/de-envelopment. Despite this, a thread of observations suggests that mechanisms similar to viral egress may be transiently used also in healthy cells. It has since been proposed that mechanisms like nuclear envelope budding (NEB) can facilitate the transport of RNA granules, aggregated proteins, inner nuclear membrane proteins, and mis-assembled NPCs. Herein, we will summarize the known roles of NEB as a physiological and intrinsic cellular feature and highlight the many unanswered questions surrounding these intriguing nuclear events.
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| 5. |
- Kohler, Verena, 1992-, et al.
(författare)
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Reversible protein assemblies in the proteostasis network in health and disease
- 2023
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Ingår i: Frontiers in Molecular Biosciences. - : Frontiers Media S.A.. - 2296-889X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- While proteins populating their native conformations constitute the functional entities of cells, protein aggregates are traditionally associated with cellular dysfunction, stress and disease. During recent years, it has become clear that large aggregate-like protein condensates formed via liquid-liquid phase separation age into more solid aggregate-like particles that harbor misfolded proteins and are decorated by protein quality control factors. The constituent proteins of the condensates/aggregates are disentangled by protein disaggregation systems mainly based on Hsp70 and AAA ATPase Hsp100 chaperones prior to their handover to refolding and degradation systems. Here, we discuss the functional roles that condensate formation/aggregation and disaggregation play in protein quality control to maintain proteostasis and why it matters for understanding health and disease.
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| 6. |
- Vazquez-Calvo, Carmela, 1983-, et al.
(författare)
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Newly imported proteins in mitochondria are particularly sensitive to aggregation
- 2023
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Ingår i: Acta Physiologica. - : John Wiley & Sons. - 1748-1708 .- 1748-1716. ; 238:3
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Tidskriftsartikel (refereegranskat)abstract
- Aim: A functional proteome is essential for life and maintained by protein quality control (PQC) systems in the cytosol and organelles. Protein aggregation is an indicator of a decline of PQC linked to aging and disease. Mitochondrial PQC is critical to maintain mitochondrial function and thus cellular fitness. How mitochondria handle aggregated proteins is not well understood. Here we tested how the metabolic status impacts on formation and clearance of aggregates within yeast mitochondria and assessed which proteins are particularly sensitive to denaturation.Methods: Confocal microscopy, electron microscopy, immunoblotting and genetics were applied to assess mitochondrial aggregate handling in response to heat shock and ethanol using the mitochondrial disaggregase Hsp78 as a marker for protein aggregates.Results: We show that aggregates formed upon heat or ethanol stress with different dynamics depending on the metabolic state. While fermenting cells displayed numerous small aggregates that coalesced into one large foci that was resistant to clearance, respiring cells showed less aggregates and cleared these aggregates more efficiently. Acute inhibition of mitochondrial translation had no effect, while preventing protein import into mitochondria by inhibition of cytosolic translation prevented aggregate formation.Conclusion: Collectively, our data show that the metabolic state of the cells impacts the dynamics of aggregate formation and clearance, and that mainly newly imported and not yet assembled proteins are prone to form aggregates. Because mitochondrial functionality is crucial for cellular metabolism, these results highlight the importance of efficient protein biogenesis to maintain the mitochondrial proteome operational during metabolic adaptations and cellular stress.
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