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Mitophagy and the mitochondrial unfolded protein response in neurodegeneration and bacterial infection.

Pellegrino MW, Haynes CM - BMC Biol. (2015)

Bottom Line: Mitochondria are highly dynamic and structurally complex organelles that provide multiple essential metabolic functions.Mitochondrial dysfunction is associated with neurodegenerative conditions such as Parkinson's disease, as well as bacterial infection.Here, we explore the roles of mitochondrial autophagy (mitophagy) and the mitochondrial unfolded protein response (UPR(mt)) in the response to mitochondrial dysfunction, focusing in particular on recent evidence on the role of mitochondrial import efficiency in the regulation of these stress pathways and how they may interact to protect the mitochondrial pool while initiating an innate immune response to protect against bacterial pathogens.

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ABSTRACT
Mitochondria are highly dynamic and structurally complex organelles that provide multiple essential metabolic functions. Mitochondrial dysfunction is associated with neurodegenerative conditions such as Parkinson's disease, as well as bacterial infection. Here, we explore the roles of mitochondrial autophagy (mitophagy) and the mitochondrial unfolded protein response (UPR(mt)) in the response to mitochondrial dysfunction, focusing in particular on recent evidence on the role of mitochondrial import efficiency in the regulation of these stress pathways and how they may interact to protect the mitochondrial pool while initiating an innate immune response to protect against bacterial pathogens.

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The ATFS-1-mediated mitochondrial unfolded protein response. The UPRmt is a protective transcriptional response to the accumulation of unfolded proteins or respiratory chain dysfunction that promotes adaptation and survival during mitochondrial dysfunction. Cells utilize the transcription factor ATFS-1 to monitor mitochondrial function and adjust transcription accordingly. Like PINK1, ATFS-1 is imported into mitochondria and quickly degraded in healthy cells, but accumulates in the cytosol during mitochondrial stress due to respiratory chain dysfunction, unfolded protein accumulation or high levels of reactive oxygen species, when mitochondrial import efficiency is impaired. Because ATFS-1 has a nuclear localization sequence (NLS), as well as its mitochondrial localization sequence (MTS), this causes it to localize to the nucleus, where it induces the transcription of genes involved in mitochondrial protein homeostasis, reactive oxygen species (ROS) and small molecule detoxification, glycolysis, and innate immunity.
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Fig2: The ATFS-1-mediated mitochondrial unfolded protein response. The UPRmt is a protective transcriptional response to the accumulation of unfolded proteins or respiratory chain dysfunction that promotes adaptation and survival during mitochondrial dysfunction. Cells utilize the transcription factor ATFS-1 to monitor mitochondrial function and adjust transcription accordingly. Like PINK1, ATFS-1 is imported into mitochondria and quickly degraded in healthy cells, but accumulates in the cytosol during mitochondrial stress due to respiratory chain dysfunction, unfolded protein accumulation or high levels of reactive oxygen species, when mitochondrial import efficiency is impaired. Because ATFS-1 has a nuclear localization sequence (NLS), as well as its mitochondrial localization sequence (MTS), this causes it to localize to the nucleus, where it induces the transcription of genes involved in mitochondrial protein homeostasis, reactive oxygen species (ROS) and small molecule detoxification, glycolysis, and innate immunity.

Mentions: Regulation of the UPRmt is much better understood in Carnorhabditis elegans, in which it is regulated by the bZip transcription factor ATFS-1, first identified in a genome-wide screen for genes required for the transcriptional induction of mitochondrial chaperones during mitochondrial stress [40]. Like PINK1, ATFS-1 has an amino-terminal MTS and is constitutively imported into healthy mitochondria, where it is processed and degraded by the Lon protease [9,13,41]. However, unlike PINK1, ATFS-1 also has a nuclear localization sequence. Where mitochondrial dysfunction is caused by impairment of mitochondrial chaperones and proteases, mutations to respiratory chain genes [41,42], exposure to respiratory chain inhibitors, including antimycin [43-45], mitochondrial ribosome impairment [46], high levels of ROS, or exposure to ethidium bromide [44,47], mitochondrial import efficiency is slowed [45], causing ATFS-1 to accumulate in the cytosol [41] (FigureĀ 2). Because of its nuclear localization sequence, rather than being degraded in the cytosol [45], ATFS-1 migrates to the nucleus where it induces transcription of over 400 genes that constitute the UPRmt. Included in this transcriptional program are mitochondrial proteases and chaperones, mitochondrial fission components, the mitochondrial protein import machinery, anti-oxidant genes and the glycolysis machinery [41].Figure 2


Mitophagy and the mitochondrial unfolded protein response in neurodegeneration and bacterial infection.

Pellegrino MW, Haynes CM - BMC Biol. (2015)

The ATFS-1-mediated mitochondrial unfolded protein response. The UPRmt is a protective transcriptional response to the accumulation of unfolded proteins or respiratory chain dysfunction that promotes adaptation and survival during mitochondrial dysfunction. Cells utilize the transcription factor ATFS-1 to monitor mitochondrial function and adjust transcription accordingly. Like PINK1, ATFS-1 is imported into mitochondria and quickly degraded in healthy cells, but accumulates in the cytosol during mitochondrial stress due to respiratory chain dysfunction, unfolded protein accumulation or high levels of reactive oxygen species, when mitochondrial import efficiency is impaired. Because ATFS-1 has a nuclear localization sequence (NLS), as well as its mitochondrial localization sequence (MTS), this causes it to localize to the nucleus, where it induces the transcription of genes involved in mitochondrial protein homeostasis, reactive oxygen species (ROS) and small molecule detoxification, glycolysis, and innate immunity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4384303&req=5

Fig2: The ATFS-1-mediated mitochondrial unfolded protein response. The UPRmt is a protective transcriptional response to the accumulation of unfolded proteins or respiratory chain dysfunction that promotes adaptation and survival during mitochondrial dysfunction. Cells utilize the transcription factor ATFS-1 to monitor mitochondrial function and adjust transcription accordingly. Like PINK1, ATFS-1 is imported into mitochondria and quickly degraded in healthy cells, but accumulates in the cytosol during mitochondrial stress due to respiratory chain dysfunction, unfolded protein accumulation or high levels of reactive oxygen species, when mitochondrial import efficiency is impaired. Because ATFS-1 has a nuclear localization sequence (NLS), as well as its mitochondrial localization sequence (MTS), this causes it to localize to the nucleus, where it induces the transcription of genes involved in mitochondrial protein homeostasis, reactive oxygen species (ROS) and small molecule detoxification, glycolysis, and innate immunity.
Mentions: Regulation of the UPRmt is much better understood in Carnorhabditis elegans, in which it is regulated by the bZip transcription factor ATFS-1, first identified in a genome-wide screen for genes required for the transcriptional induction of mitochondrial chaperones during mitochondrial stress [40]. Like PINK1, ATFS-1 has an amino-terminal MTS and is constitutively imported into healthy mitochondria, where it is processed and degraded by the Lon protease [9,13,41]. However, unlike PINK1, ATFS-1 also has a nuclear localization sequence. Where mitochondrial dysfunction is caused by impairment of mitochondrial chaperones and proteases, mutations to respiratory chain genes [41,42], exposure to respiratory chain inhibitors, including antimycin [43-45], mitochondrial ribosome impairment [46], high levels of ROS, or exposure to ethidium bromide [44,47], mitochondrial import efficiency is slowed [45], causing ATFS-1 to accumulate in the cytosol [41] (FigureĀ 2). Because of its nuclear localization sequence, rather than being degraded in the cytosol [45], ATFS-1 migrates to the nucleus where it induces transcription of over 400 genes that constitute the UPRmt. Included in this transcriptional program are mitochondrial proteases and chaperones, mitochondrial fission components, the mitochondrial protein import machinery, anti-oxidant genes and the glycolysis machinery [41].Figure 2

Bottom Line: Mitochondria are highly dynamic and structurally complex organelles that provide multiple essential metabolic functions.Mitochondrial dysfunction is associated with neurodegenerative conditions such as Parkinson's disease, as well as bacterial infection.Here, we explore the roles of mitochondrial autophagy (mitophagy) and the mitochondrial unfolded protein response (UPR(mt)) in the response to mitochondrial dysfunction, focusing in particular on recent evidence on the role of mitochondrial import efficiency in the regulation of these stress pathways and how they may interact to protect the mitochondrial pool while initiating an innate immune response to protect against bacterial pathogens.

View Article: PubMed Central - PubMed

ABSTRACT
Mitochondria are highly dynamic and structurally complex organelles that provide multiple essential metabolic functions. Mitochondrial dysfunction is associated with neurodegenerative conditions such as Parkinson's disease, as well as bacterial infection. Here, we explore the roles of mitochondrial autophagy (mitophagy) and the mitochondrial unfolded protein response (UPR(mt)) in the response to mitochondrial dysfunction, focusing in particular on recent evidence on the role of mitochondrial import efficiency in the regulation of these stress pathways and how they may interact to protect the mitochondrial pool while initiating an innate immune response to protect against bacterial pathogens.

Show MeSH
Related in: MedlinePlus