The proteasome: friend and foe of mitochondrial biogenesis

Krämer, Lena; Groh, Carina; Herrmann, J. M.

doi:10.1002/1873-3468.14010

Cited by 28 publications

(30 citation statements)

References 148 publications

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“…Thus, at normal Mia40 levels, a fraction of newly synthesized mitochondrial proteins is apparently never imported but retained in the cytosol and finally degraded. Recent studies indeed directly demonstrated the competition of the Mia40-mediated import and proteasomal degradation (Kowalski et al, 2018, Krämer, Groh et al, 2020, Mohanraj et al, 2019). Thus, increased Mia40 levels presumably speed up the import of certain proteins and thus might reduce their burden on cytosolic proteostasis.…”

Section: Discussionmentioning

confidence: 95%

Increased levels of the mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol

Schlagowski

Knöringer

Morlot

et al. 2021

Preprint

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The formation of protein aggregates is a hallmark of neurodegenerative diseases. Observations on patient material and model systems demonstrated links between aggregate formation and declining mitochondrial functionality, but the causalities remained unclear. We used yeast as model system to analyze the relevance of mitochondrial processes for the behavior of an aggregation-prone polyQ protein derived from human huntingtin. Induction of Q97-GFP rapidly leads to insoluble cytosolic aggregates and cell death. Although this aggregation impairs mitochondrial respiration only slightly, it interferes with efficient import of mitochondrial precursor proteins. Mutants in the import component Mia40 are hypersensitive to Q97-GFP. Even more surprisingly, Mia40 overexpression strongly suppresses the formation of toxic Q97-GFP aggregates both in yeast and in human cells. Based on these observations, we propose that the posttranslational import into mitochondria competes with aggregation-prone cytosolic proteins for chaperones and proteasome capacity. Owing to its rate-limiting role for mitochondrial protein import, Mia40 acts as a regulatory component in this competition. This role of Mia40 as dynamic regulator in mitochondrial biogenesis can apparently be exploited to stabilize cytosolic proteostasis.

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Section: Discussionmentioning

confidence: 95%

Increased levels of the mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol

Schlagowski

Knöringer

Morlot

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, at normal Mia40 levels, a fraction of newly synthesized mitochondrial proteins is apparently never imported but retained in the cytosol and finally degraded. Recent studies indeed directly demonstrated the competition of the Mia40‐mediated import and proteasomal degradation (Kowalski et al , 2018; Mohanraj et al , 2019; Krämer, Groh et al , 2020). Thus, increased Mia40 levels presumably speed up the import of certain proteins and thus might reduce their burden on cytosolic proteostasis (Fig 8E, middle panel). The Mia40 pathway is only one out of several import routes into mitochondria.…”

Section: Discussionmentioning

confidence: 97%

Increased levels of mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol

et al. 2021

Self Cite

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The formation of protein aggregates is a hallmark of neurodegenerative diseases. Observations on patient samples and model systems demonstrated links between aggregate formation and declining mitochondrial functionality, but causalities remain unclear. We used Saccharomyces cerevisiae to analyze how mitochondrial processes regulate the behavior of aggregation‐prone polyQ protein derived from human huntingtin. Expression of Q97‐GFP rapidly led to insoluble cytosolic aggregates and cell death. Although aggregation impaired mitochondrial respiration only slightly, it considerably interfered with the import of mitochondrial precursor proteins. Mutants in the import component Mia40 were hypersensitive to Q97‐GFP, whereas Mia40 overexpression strongly suppressed the formation of toxic Q97‐GFP aggregates both in yeast and in human cells. Based on these observations, we propose that the post‐translational import of mitochondrial precursor proteins into mitochondria competes with aggregation‐prone cytosolic proteins for chaperones and proteasome capacity. Mia40 regulates this competition as it has a rate‐limiting role in mitochondrial protein import. Therefore, Mia40 is a dynamic regulator in mitochondrial biogenesis that can be exploited to stabilize cytosolic proteostasis.

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“…Proteasomal degradation of ER and mitochondrial proteins (Figure 3) is often summarized under the umbrella terms ERAD (for ER-associated degradation) and MAD (for mitochondria-associated degradation) [86][87][88][89]. The components and underlying mechanisms of ERAD are rather well understood, and even structures of the ERAD machinery were recently published [90].…”

Section: Destructive Targeting Via Erad and Madmentioning

confidence: 99%

ER-SURF: Riding the Endoplasmic Reticulum Surface to Mitochondria

Koch

Schuldiner

Herrmann

2021

IJMS

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Most mitochondrial proteins are synthesized in the cytosol and targeted to the mitochondrial surface in a post-translational manner. The surface of the endoplasmic reticulum (ER) plays an active role in this targeting reaction. ER-associated chaperones interact with certain mitochondrial membrane protein precursors and transfer them onto receptor proteins of the mitochondrial surface in a process termed ER-SURF. ATP-driven proteins in the membranes of mitochondria (Msp1, ATAD1) and the ER (Spf1, P5A-ATPase) serve as extractors for the removal of mislocalized proteins. If the re-routing to mitochondria fails, precursors can be degraded by ER or mitochondria-associated degradation (ERAD or MAD respectively) in a proteasome-mediated reaction. This review summarizes the current knowledge about the cooperation of the ER and mitochondria in the targeting and quality control of mitochondrial precursor proteins.

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The proteasome: friend and foe of mitochondrial biogenesis

Cited by 28 publications

References 148 publications

Increased levels of the mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol

Increased levels of the mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol

Increased levels of mitochondrial import factor Mia40 prevent the aggregation of polyQ proteins in the cytosol

ER-SURF: Riding the Endoplasmic Reticulum Surface to Mitochondria

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