Dynamic organization of the mitochondrial protein import machinery

Straub, Sebastian; Stiller, Sebastian B.; Wiedemann, Nils; Pfanner, Nikolaus

doi:10.1515/hsz-2016-0145

Cited by 32 publications

(15 citation statements)

References 228 publications

(252 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One of the first quality checkups are ensured by the different protein import complexes -such as the translocase of the outer membrane (TOM), the translocases of the inner membrane TIM23 and TIM22 -importing nuclear encoded proteins into their target submitochondrial compartment (reviewed in Straub et al, 2016;Wiedemann and Pfanner, 2017). A critical contribution to the integrity of the mitochondrial proteome is made by chaperones, which assist in the folding of unfolded or wrongly folded proteins, and proteases, which digest aggregation-prone and dysfunctional proteins (reviewed in Koppen and Langer 2007;Voos et al, 2016).…”

Section: Mitochondrial Quality Control -Many Levels Ensure the Functimentioning

confidence: 99%

How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways

Zimmermann

Reichert

2017

Biological Chemistry

View full text Add to dashboard Cite

Mitochondria are indispensable cellular organelles providing ATP and numerous other essential metabolites to ensure cell survival. Reactive oxygen species (ROS), which are formed as side reactions during oxidative phosphorylation or by external agents, induce molecular damage in mitochondrial proteins, lipids/ membranes and DNA. To cope with this and other sorts of organellar stress, a multi-level quality control system exists to maintain cellular homeostasis. One critical level of mitochondrial quality control is the removal of damaged mitochondria by mitophagy. This process utilizes parts of the general autophagy machinery, e.g. for the formation of autophagosomes but also employs mitophagy-specific factors. Depending on the proteins utilized mitophagy is divided into receptor-mediated and ubiquitin-mediated mitophagy. So far, at least seven receptor proteins are known to be required for mitophagy under different experimental conditions. In contrast to receptor-mediated pathways, the Pink-Parkin-dependent pathway is currently the best characterized ubiquitin-mediated pathway. Recently two additional ubiquitin-mediated pathways with distinctive similarities and differences were unraveled. We will summarize the current state of knowledge about these multiple pathways, explain their mechanism, and describe the regulation and crosstalk between these pathways. Finally, we will review recent evidence for the evolutionary conservation of ubiquitin-mediated mitophagy pathways.

show abstract

Section: Mitochondrial Quality Control -Many Levels Ensure the Functimentioning

confidence: 99%

How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways

Zimmermann

Reichert

2017

Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…To ensure precise protein targeting, a versatile system integrates many protein sorting, translocation and folding machineries (figure 1 b ) [7,19–24]. The translocase of the outer membrane (TOM) is a multi-subunit complex that serves as the receptor and entry gate for the vast majority of mitochondrial proteins.…”

Section: Introductionmentioning

confidence: 99%

Control of mitochondrial biogenesis and function by the ubiquitin–proteasome system

2017

View full text Add to dashboard Cite

Mitochondria are pivotal organelles in eukaryotic cells. The complex proteome of mitochondria comprises proteins that are encoded by nuclear and mitochondrial genomes. The biogenesis of mitochondrial proteins requires their transport in an unfolded state with a high risk of misfolding. The mislocalization of mitochondrial proteins is deleterious to the cell. The electron transport chain in mitochondria is a source of reactive oxygen species that damage proteins. Mitochondrial dysfunction is linked to many pathological conditions and, together with the loss of cellular protein homeostasis (proteostasis), are hallmarks of ageing and ageing-related degeneration diseases. The pathogenesis of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, has been associated with mitochondrial and proteostasis failure. Thus, mitochondrial proteins require sophisticated surveillance mechanisms. Although mitochondria form a proteasome-exclusive compartment, multiple lines of evidence indicate a crucial role for the cytosolic ubiquitin–proteasome system (UPS) in the quality control of mitochondrial proteins. The proteasome affects mitochondrial proteins at stages of their biogenesis and maturity. The effects of the UPS go beyond the removal of damaged proteins and include the adjustment of mitochondrial proteome composition, the regulation of organelle dynamics and the protection of cellular homeostasis against mitochondrial failure. In turn, mitochondrial activity and mitochondrial dysfunction adjust the activity of the UPS, with implications at the cellular level.

show abstract

“…Thus, a mitochondrion must coordinate the expression of the nuclear genome while also supporting the transcription and translation of its own gene products. Mitochondria are equipped with a protein import machinery (PIM) that facilitates the translocation of nuclear-encoded proteins (37), as well as a mito- chondrion-specific UPR (UPR mt ) that strives to maintain proteostasis (31,43).…”

Section: Discussionmentioning

confidence: 99%

Effect of Tim23 knockdown in vivo on mitochondrial protein import and retrograde signaling to the UPR^mt in muscle

Oliveira

Hood

2018

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

The mitochondrial unfolded protein response (UPR) is a protein quality control mechanism that strives to achieve proteostasis in the face of misfolded proteins. Because of the reliance of mitochondria on both the nuclear and mitochondrial genomes, a perturbation of the coordination of these genomes results in a mitonuclear imbalance in which holoenzymes are unable to assume mature stoichiometry and thereby activates the UPR. Thus, we sought to perturb this genomic coordination by using a systemic antisense oligonucleotide (in vivo morpholino) targeted to translocase of the inner membrane channel subunit 23 (Tim23), the major channel of the inner membrane. This resulted in a 40% reduction in Tim23 protein content, a 32% decrease in matrix-destined protein import, and a trend to elevate reactive oxygen species (ROS) emission under maximal respiration conditions. This import defect activated the C/EBP homologous protein (CHOP) branch of the UPR, as evident from increases in caseinolytic mitochondrial matrix peptidase proteolytic subunit (ClpP) and chaperonin 10 (cpn10) but not the activating transcription factor 5 (ATF5) arm. Thus, in the face of proteotoxic stress, CHOP and ATF5 could be activated independently to regain proteostasis. Our second aim was to investigate the role of proteolytically derived peptides in mediating retrograde signaling. Peptides released from the mitochondrion following basal proteolysis were isolated and incubated with import reactions. Dose- and time-dependent effect of peptides on protein import was observed. Our data suggest that mitochondrial proteolytic byproducts exert an inhibitory effect on protein import, possibly to reduce excessive protein import as a potential negative feedback mechanism. The inhibition of import into the organelle also serves a retrograde function, possibly via ROS emission, to modify nuclear gene expression and ultimately improve folding capacity.

show abstract

Dynamic organization of the mitochondrial protein import machinery

Cited by 32 publications

References 228 publications

How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways

How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways

Control of mitochondrial biogenesis and function by the ubiquitin–proteasome system

Effect of Tim23 knockdown in vivo on mitochondrial protein import and retrograde signaling to the UPR^mt in muscle

Contact Info

Product

Resources

About

Dynamic organization of the mitochondrial protein import machinery

Cited by 32 publications

References 228 publications

How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways

How to get rid of mitochondria: crosstalk and regulation of multiple mitophagy pathways

Control of mitochondrial biogenesis and function by the ubiquitin–proteasome system

Effect of Tim23 knockdown in vivo on mitochondrial protein import and retrograde signaling to the UPRmt in muscle

Contact Info

Product

Resources

About

Effect of Tim23 knockdown in vivo on mitochondrial protein import and retrograde signaling to the UPR^mt in muscle