Stendomycin selectively inhibits TIM23-dependent mitochondrial protein import

Filipuzzi, Ireos; Steffen, Janos; Germain, Mitchel; Goepfert, Laetitia; Conti, Michael; Potting, Christoph; Cerino, Raffaele; Pfeifer, Martin; Krastel, Philipp; Hoepfner, Dominic; Bastien, Julie; Koehler, Carla M.; Helliwell, Stephen B.

doi:10.1038/nchembio.2493

Cited by 24 publications

(18 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Stendomycin reduced the import of proteins into the IMM, IMS, and matrix by Tim23 both in vitro and in vivo. However, interestingly, it had no effect on steady-state PINK1 import (Filipuzzi et al, 2017), which is consistent with our Tim23 knockdown experiments. Recent analysis of another PARL substrate, STARD7, also revealed that PARL-mediated STARD7 cleavage was observed after Tim23 knockdown (Saita et al, 2018).…”

Section: Discussionsupporting

confidence: 90%

“…Analogous to the development of small compounds to enhance PINK1 kinase activity as a potential treatment for PD (Hertz et al, 2013), manipulation of PINK1 import may be another druggable target to augment PINK1 activity. Among such drug screens, stendomycin, a natural lipopeptide produced by Streptomyces hygroscopicus, has been recently identified as an inhibitor of Tim23-dependent mitochondrial protein import (Filipuzzi et al, 2017). Stendomycin reduced the import of proteins into the IMM, IMS, and matrix by Tim23 both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1

et al. 2019

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Moreover, our data emphasize that this technique is useful to study the involvement of other proteins, such as Sirt3 and Sirt5, in the retrograde signaling pathway with high resolution. We also highlight that this approach is applicable to screen compounds that target mitochondrial protein import, such as stendomycin [31].…”

Section: Discussionmentioning

confidence: 99%

Visualization of Sirtuin 4 Distribution between Mitochondria and the Nucleus, Based on Bimolecular Fluorescence Self-Complementation

Ramadani‐Muja

Gottschalk

Pfeil

et al. 2019

Cells

View full text Add to dashboard Cite

Mitochondrial sirtuins (Sirts) control important cellular processes related to stress. Despite their regulatory importance, however, the dynamics and subcellular distributions of Sirts remain debatable. Here, we investigate the subcellular localization of sirtuin 4 (Sirt4), a sirtuin variant with a mitochondrial targeting sequence (MTS), by expressing Sirt4 fused to the superfolder green fluorescent protein (Sirt4-sfGFP) in HeLa and pancreatic β-cells. Super resolution fluorescence microscopy revealed the trapping of Sirt4-sfGFP to the outer mitochondrial membrane (OMM), possibly due to slow mitochondrial import kinetics. In many cells, Sirt4-sfGFP was also present within the cytosol and nucleus. Moreover, the expression of Sirt4-sfGFP induced mitochondrial swelling in HeLa cells. In order to bypass these effects, we applied the self-complementing split fluorescent protein (FP) technology and developed mito-STAR (mitochondrial sirtuin 4 tripartite abundance reporter), a tripartite probe for the visualization of Sirt4 distribution between mitochondria and the nucleus in single cells. The application of mito-STAR proved the importation of Sirt4 into the mitochondrial matrix and demonstrated its localization in the nucleus under mitochondrial stress conditions. Moreover, our findings highlight that the self-complementation of split FP is a powerful technique to study protein import efficiency in distinct cellular organelles.

show abstract

“…Further validation of kinetin activity, especially in vivo, is expected. Although the activation of PINK1 kinase activity is closely related to its import regulation, as discussed above, there are no reports of small molecules targeting PINK1 import so far, although attempts are being made in this promising new direction [ 82 ].…”

Section: In Vivo Relevance and Potential For Drug Discoverymentioning

confidence: 99%

PINK1 import regulation; a fine system to convey mitochondrial stress to the cytosol

2018

View full text Add to dashboard Cite

Insights from inherited forms of parkinsonism suggest that insufficient mitophagy may be one etiology of the disease. PINK1/Parkin-dependent mitophagy, which helps maintain a healthy mitochondrial network, is initiated by activation of the PINK1 kinase specifically on damaged mitochondria. Recent investigation of this process reveals that import of PINK1 into mitochondria is regulated and yields a stress-sensing mechanism. In this review, we focus on the mechanisms of mitochondrial stress-dependent PINK1 activation that is exerted by regulated import of PINK1 into different mitochondrial compartments and how this offers strategies to pharmacologically activate the PINK1/Parkin pathway.

show abstract

Stendomycin selectively inhibits TIM23-dependent mitochondrial protein import

Cited by 24 publications

References 26 publications

Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1

Reciprocal Roles of Tom7 and OMA1 during Mitochondrial Import and Activation of PINK1

Visualization of Sirtuin 4 Distribution between Mitochondria and the Nucleus, Based on Bimolecular Fluorescence Self-Complementation

PINK1 import regulation; a fine system to convey mitochondrial stress to the cytosol

Contact Info

Product

Resources

About