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2015 ; 11
(4
): 595-606
Nephropedia Template TP
Wang Y
; Serricchio M
; Jauregui M
; Shanbhag R
; Stoltz T
; Di Paolo CT
; Kim PK
; McQuibban GA
Autophagy
2015[Apr]; 11
(4
): 595-606
PMID25915564
show ga
The selective degradation of mitochondria by the process of autophagy, termed
mitophagy, is one of the major mechanisms of mitochondrial quality control. The
best-studied mitophagy pathway is the one mediated by PINK1 and PARK2/Parkin.
From recent studies it has become clear that ubiquitin-ligation plays a pivotal
role and most of the focus has been on the role of ubiquitination of
mitochondrial proteins in mitophagy. Even though ubiquitination is a reversible
process, very little is known about the role of deubiquitinating enzymes (DUBs)
in mitophagy. Here, we report that 2 mitochondrial DUBs, USP30 and USP35,
regulate PARK2-mediated mitophagy. We show that USP30 and USP35 can delay
PARK2-mediated mitophagy using a quantitative mitophagy assay. Furthermore, we
show that USP30 delays mitophagy by delaying PARK2 recruitment to the
mitochondria during mitophagy. USP35 does not delay PARK2 recruitment, suggesting
that it regulates mitophagy through an alternative mechanism. Interestingly,
USP35 only associates with polarized mitochondria, and rapidly translocates to
the cytosol during CCCP-induced mitophagy. It is clear that PARK2-mediated
mitophagy is regulated at many steps in this important quality control pathway.
Taken together, these findings demonstrate an important role of
mitochondrial-associated DUBs in mitophagy. Because defects in mitochondria
quality control are implicated in many neurodegenerative disorders, our study
provides clear rationales for the design and development of drugs for the
therapeutic treatment of neurodegenerative diseases such as Parkinson and
Alzheimer diseases.
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