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

Sekine, Shiori; Youle, Richard J.

doi:10.1186/s12915-017-0470-7

Cited by 249 publications

(226 citation statements)

References 86 publications

(160 reference statements)

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“…Pink1 was discovered to have a mitochondrial targeting sequence (MTS) which directs the protein into the correct mitochondrial subcompartment. Pink1 is imported into the mitochondrion as a precursor, which is cleaved within the matrix by the protease MPPα/β . While it is thought that the N‐terminus of Pink1 has some involvement in mitochondrial targeting, it has also been discovered that there are cleavage sites situated within the N‐terminus which are cleaved by the MPP proteases.…”

Section: Quality Control In the Mitochondrionmentioning

confidence: 99%

“…Pink1 is imported into the mitochondrion as a precursor, which is cleaved within the matrix by the protease MPPα/β. 62 While it is thought that the N-terminus of Pink1 has some involvement in mitochondrial targeting, it has also been discovered that there are cleavage sites situated within the N-terminus which are cleaved by the MPP proteases. The import of Pink1 through the Tom complex is driven by the mitochondrial membrane potential, and once through, Pink1 then transports across the IMM via the Tim complexes.…”

Section: Mitophagymentioning

confidence: 99%

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Mitochondrial integrity in neurodegeneration

2019

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Summary The mitochondrion is a unique organelle with a diverse range of functions. Mitochondrial dysfunction is a key pathological process in several neurodegenerative diseases. Mitochondria are mostly important for energy production; however, they also have roles in Ca 2+ homeostasis, ROS production, and apoptosis. There are two major systems in place, which regulate mitochondrial integrity, mitochondrial dynamics, and mitophagy. These two processes remove damaged mitochondria from cells and protect the functional mitochondrial population. These quality control systems often become dysfunctional during neurodegenerative diseases, such as Parkinson's and Alzheimer's disease, causing mitochondrial dysfunction and severe neurological symptoms.

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Section: Quality Control In the Mitochondrionmentioning

confidence: 99%

Section: Mitophagymentioning

confidence: 99%

Mitochondrial integrity in neurodegeneration

2019

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“…Under basal conditions, PINK1 is transported into the mitochondrial matrix through the translocases of the outer membrane, TOM20 and TOM23, the translocation channel TOM40, and the translocase of inner membrane TIM23. Inside the mitochondrial matrix, PINK1 is cleaved by a mitochondrial processing peptidase (MPP) and a rhomboid protease, PARL . The cleaved PINK1 is then re‐transported into the cytosol and degraded by the ubiquitin (Ub) proteasome system (UPS) …”

Section: Parkinson's Disease Relevant Protein Kinasesmentioning

confidence: 99%

“…Inside the mitochondrial matrix, PINK1 is cleaved by a mitochondrial processing peptidase (MPP) and a rhomboid protease, PARL. [170][171][172] The cleaved PINK1 is then re-transported into the cytosol and degraded by the ubiquitin (Ub) proteasome system (UPS). 171 When PINK1 transport through TOM is hindered, for instance by a depolarized mitochondria membrane potential (MMP), it and Ser402.…”

Section: Pten-induced Kinase 1 (Pink1)mentioning

confidence: 99%

Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

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Mitochondria are highly integrated organelles that are crucial to cell adaptation and mitigating adverse physiology. Recent studies demonstrate that fundamental signal transduction pathways incorporate mitochondrial substrates into their biological programs. Reversible phosphorylation is emerging as a useful mechanism to modulate mitochondrial function in accordance with cellular changes. Critical serine/threonine protein kinases, such as the c‐Jun N‐terminal kinase (JNK), protein kinase A (PKA), PTEN‐induced kinase‐1 (PINK1), and AMP‐dependent protein kinase (AMPK), readily translocate to the outer mitochondrial membrane (OMM), the interface of mitochondria‐cell communication. OMM protein kinases phosphorylate diverse mitochondrial substrates that have discrete effects on organelle dynamics, protein import, respiratory complex activity, antioxidant capacity, and apoptosis. OMM phosphorylation events can be tempered through the actions of local protein phosphatases, such as mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) and protein phosphatase 2A (PP2A), to regulate the extent and duration of signaling. The central mediators of OMM signal transduction are the scaffold proteins because the relative abundance of these accessory proteins determines the magnitude and duration of a signaling event on the mitochondrial surface, which dictates the biological outcome of a local signal transduction pathway. The concentrations of scaffold proteins, such as A‐kinase anchoring proteins (AKAPs) and Sab (or SH3 binding protein 5—SH3BP5), have been shown to influence neuronal survival and vulnerability, respectively, in models of Parkinson's disease (PD), highlighting the importance of OMM signaling to health and disease. Despite recent progress, much remains to be discovered concerning the mechanisms of OMM signaling. Nonetheless, enhancing beneficial OMM signaling events and inhibiting detrimental protein‐protein interactions on the mitochondrial surface may represent highly selective approaches to restore mitochondrial health and homeostasis and mitigate organelle dysfunction in conditions such as PD.

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“…In the case of damage to the mitochondria, the mitochondrial membrane is depolarized, and the voltage of the outer membrane is reduced. At this time, PINK1 cannot be immediately degraded, but stabilizes the outer membrane of the mitochondria and recruits Parkin to mitochondria . Parkin is an E3 ubiquitin ligase that can ubiquitinate mitochondrial proteins, such as VDAC1, forming a complex that cooperates with the kinesin‐like proteins to complete mitophagy .…”

Section: Introductionmentioning

confidence: 99%

Novel mitochondrion‐targeting copper(II) complex induces HK2 malfunction and inhibits glycolysis via Drp1‐mediating mitophagy in HCC

Guo

Jin

et al. 2020

J Cellular Molecular Medi

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[Cu(ttpy‐tpp)Br2]Br (abbreviated as CTB) is a novel mitochondrion‐targeting copper(II) complex synthesized by our research group, which contains tri‐phenyl‐phosphonium (TPP) groups as its lipophilic property. In this study, we explored how CTB affects mitochondrial functions and exerts its anti‐tumour activity. Multiple functional and molecular analyses including Seahorse XF Bioanalyzer Platform, Western blot, immunofluorescence analysis, co‐immunoprecipitation and transmission electron microscopy were used to elucidate the underlying mechanisms. Human hepatoma cells were subcutaneously injected into right armpit of male nude mice for evaluating the effects of CTB in vivo. We discovered that CTB inhibited aerobic glycolysis and cell acidification by impairing the activity of HK2 in hepatoma cells, accompanied by dissociation of HK2 from mitochondria. The modification of HK2 not only led to the complete dissipation of mitochondrial membrane potential (MMP) but also promoted the opening of mitochondrial permeability transition pore (mPTP), contributing to the activation of mitophagy. In addition, CTB co‐ordinately promoted dynamin‐related protein 1 (Drp1) recruitment in mitochondria to induce mitochondrial fission. Our findings established a previously unrecognized role for copper complex in aerobic glycolysis of tumour cells, revealing the interaction between mitochondrial HK2‐mediated mitophagy and Drp1‐regulated mitochondrial fission.

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

Cited by 249 publications

References 86 publications

Mitochondrial integrity in neurodegeneration

Mitochondrial integrity in neurodegeneration

Phosphoregulation on mitochondria: Integration of cell and organelle responses

Novel mitochondrion‐targeting copper(II) complex induces HK2 malfunction and inhibits glycolysis via Drp1‐mediating mitophagy in HCC

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