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PINK1 Content in Mitochondria is Regulated by ER-Associated Degradation
- Publication Year :
- 2019
-
Abstract
- Maintaining a pool of functional mitochondria requires degradation of damaged ones within the cell. PINK1 is critical in this quality-control process: loss of mitochondrial membrane potential causes PINK1 to accumulate on the mitochondrial surface, triggering mitophagy. However, little is known about how PINK1 is regulated. Recently, we showed that PINK1 content is kept low in healthy mitochondria by continuous ubiquitination and proteasomal degradation of its mature form via a mechanism inconsistent with the proposed N-end rule process. Using both human female and monkey cell lines, we now demonstrate that once generated within the mitochondria, 52 kDa PINK1 adopts a mitochondrial topology most consistent with it being at the mitochondrial–endoplasmic reticulum (ER) interface. From this particular submitochondrial location, PINK1 interacts with components of the ER-associated degradation pathway, such as the E3 ligases gp78 and HRD1, which cooperate to catalyze PINK1 ubiquitination. The valosin-containing protein and its cofactor, UFD1, then target ubiquitinated PINK1 for proteasomal degradation. Our data show that PINK1 in healthy mitochondria is negatively regulated via an interplay between mitochondria and ER, and shed light on how this mitochondrial protein gains access to the proteasome. SIGNIFICANCE STATEMENT Regulation of mitochondrial content of PINK1, a contributor to mitophagy, is an important area of research. Recently, we found that PINK1 content is kept low in healthy mitochondria by continuous ubiquitination and proteasomal degradation. We now extend and refine this novel finding by showing that PINK1 localizes at the mitochondrial–endoplasmic reticulum (ER) interface, from where it interacts with the ER-associated degradation machinery, which catalyzes its ubiquitination and transfer to the proteasome. Thus, these data show that PINK1 in healthy mitochondria is negatively regulated via a mitochondria and ER interplay, and how this mitochondrial protein gains access to the proteasome.
- Subjects :
- Proteasome Endopeptidase Complex
Ubiquitin-Protein Ligases
Cell
PINK1
Endoplasmic-reticulum-associated protein degradation
Mitochondrion
Endoplasmic Reticulum
03 medical and health sciences
Mice
0302 clinical medicine
Ubiquitin
Valosin Containing Protein
Cell Line, Tumor
Mitophagy
Chlorocebus aethiops
medicine
Animals
Humans
Research Articles
030304 developmental biology
Membrane potential
0303 health sciences
biology
Chemistry
General Neuroscience
Intracellular Signaling Peptides and Proteins
Ubiquitination
Cell biology
Mitochondria
Receptors, Autocrine Motility Factor
medicine.anatomical_structure
HEK293 Cells
Proteasome
COS Cells
Proteolysis
biology.protein
Protein Kinases
030217 neurology & neurosurgery
HeLa Cells
Protein Binding
Subjects
Details
- ISSN :
- 02706474
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....6e625a05931a62eb5f7927e8d2269bcf