Temporal integration of mitochondrial stress signals by the PINK1:Parkin pathway
Abstract Background The PINK1:Parkin pathway regulates the autophagic removal of damaged and dysfunctional mitochondria. While the response of this pathway to complete loss of ΔΨm, as caused by high concentrations of mitochondrial ionophores, has been well characterized, it remains unclear how the p...
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doaj-f3c87354457249f4a03ec87c2c79cd5a2020-11-25T03:45:54ZengBMCBMC Molecular and Cell Biology2661-88502019-08-0120112110.1186/s12860-019-0220-5Temporal integration of mitochondrial stress signals by the PINK1:Parkin pathwayJ. Logan Bowling0Mary Catherine Skolfield1Wesley A. Riley2Andrew P. Nolin3Larissa C. Wolf4David E. Nelson5Department of Biology, Middle Tennessee State UniversityDepartment of Biology, Middle Tennessee State UniversityDepartment of Biology, Middle Tennessee State UniversityDepartment of Biology, Middle Tennessee State UniversityDepartment of Biology, Middle Tennessee State UniversityDepartment of Biology, Middle Tennessee State UniversityAbstract Background The PINK1:Parkin pathway regulates the autophagic removal of damaged and dysfunctional mitochondria. While the response of this pathway to complete loss of ΔΨm, as caused by high concentrations of mitochondrial ionophores, has been well characterized, it remains unclear how the pathway makes coherent decisions about whether to keep or purge mitochondria in situations where ΔΨm is only partially lost or exhibits fluctuations, as has been observed in response to certain types of cellular stress. Results To investigate the responses of the PINK1:Parkin pathway to mitochondrial insults of different magnitude and duration, controlled titration of the mitochondrial protonophore, CCCP, was used to manipulate ΔΨm in live cells, and the dynamics of PINK1 and Parkin recruitment was measured by fluorescence microscopy. In contrast to the stable accumulation of PINK1 and Parkin seen at completely depolarized mitochondria, partial depolarization produced a transient pulse of PINK1 stabilization and rapid loss, which was driven by small fluctuations in ΔΨm. As the rate of Parkin dissociation from the mitochondria and phospho-polyubiquitin chain removal was comparatively slow, repetitive pulses of PINK1 were able to drive a slow step-wise accumulation of Parkin and phospho-polyubiquitin leading to deferred mitophagy. Conclusion These data suggest that the PINK1:Parkin mitophagy pathway is able to exhibit distinct dynamic responses to complete and partial mitochondrial depolarization. In this way, the pathway is able to differentiate between irretrievably damaged mitochondria and those showing signs of dysfunction, promoting either rapid or delayed autophagy, respectively.http://link.springer.com/article/10.1186/s12860-019-0220-5Cell signallingMitophagyParkinPTEN-induced putative kinase 1 (PINK1)Ubiquitin |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
J. Logan Bowling Mary Catherine Skolfield Wesley A. Riley Andrew P. Nolin Larissa C. Wolf David E. Nelson |
spellingShingle |
J. Logan Bowling Mary Catherine Skolfield Wesley A. Riley Andrew P. Nolin Larissa C. Wolf David E. Nelson Temporal integration of mitochondrial stress signals by the PINK1:Parkin pathway BMC Molecular and Cell Biology Cell signalling Mitophagy Parkin PTEN-induced putative kinase 1 (PINK1) Ubiquitin |
author_facet |
J. Logan Bowling Mary Catherine Skolfield Wesley A. Riley Andrew P. Nolin Larissa C. Wolf David E. Nelson |
author_sort |
J. Logan Bowling |
title |
Temporal integration of mitochondrial stress signals by the PINK1:Parkin pathway |
title_short |
Temporal integration of mitochondrial stress signals by the PINK1:Parkin pathway |
title_full |
Temporal integration of mitochondrial stress signals by the PINK1:Parkin pathway |
title_fullStr |
Temporal integration of mitochondrial stress signals by the PINK1:Parkin pathway |
title_full_unstemmed |
Temporal integration of mitochondrial stress signals by the PINK1:Parkin pathway |
title_sort |
temporal integration of mitochondrial stress signals by the pink1:parkin pathway |
publisher |
BMC |
series |
BMC Molecular and Cell Biology |
issn |
2661-8850 |
publishDate |
2019-08-01 |
description |
Abstract Background The PINK1:Parkin pathway regulates the autophagic removal of damaged and dysfunctional mitochondria. While the response of this pathway to complete loss of ΔΨm, as caused by high concentrations of mitochondrial ionophores, has been well characterized, it remains unclear how the pathway makes coherent decisions about whether to keep or purge mitochondria in situations where ΔΨm is only partially lost or exhibits fluctuations, as has been observed in response to certain types of cellular stress. Results To investigate the responses of the PINK1:Parkin pathway to mitochondrial insults of different magnitude and duration, controlled titration of the mitochondrial protonophore, CCCP, was used to manipulate ΔΨm in live cells, and the dynamics of PINK1 and Parkin recruitment was measured by fluorescence microscopy. In contrast to the stable accumulation of PINK1 and Parkin seen at completely depolarized mitochondria, partial depolarization produced a transient pulse of PINK1 stabilization and rapid loss, which was driven by small fluctuations in ΔΨm. As the rate of Parkin dissociation from the mitochondria and phospho-polyubiquitin chain removal was comparatively slow, repetitive pulses of PINK1 were able to drive a slow step-wise accumulation of Parkin and phospho-polyubiquitin leading to deferred mitophagy. Conclusion These data suggest that the PINK1:Parkin mitophagy pathway is able to exhibit distinct dynamic responses to complete and partial mitochondrial depolarization. In this way, the pathway is able to differentiate between irretrievably damaged mitochondria and those showing signs of dysfunction, promoting either rapid or delayed autophagy, respectively. |
topic |
Cell signalling Mitophagy Parkin PTEN-induced putative kinase 1 (PINK1) Ubiquitin |
url |
http://link.springer.com/article/10.1186/s12860-019-0220-5 |
work_keys_str_mv |
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1724509008076734464 |