PINK1-Parkin a central role for PINK1 in regulating

 

PINK1-Parkin dependent Mitophagy

Revolutionary work by
the Youle laboratory initially coupled Parkin to mitophagy, and subsequent
contributions from other laboratories have defined a central role for PINK1 in
regulating Parkin succeeding mitochondrial damage. PINK1-Parkin pathway starts
by unravelling the difference between healthy and damaged mitochondria. PTEN-induced kinase1 (PINK1), a 64kDa protein contains a
mitochondrial targeting sequence (MTS) and is recruited to the mitochondria.

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In healthy mitochondria, PINK1 is constitutively imported
through the outer membrane via the TOM complex, and partially through the
inner mitochondrial membrane via the TIM complex. PINK1 then spans the inner
membrane and is cleaved from 64-kDa to 60-kDa. It is then cleaved by inner
mitochondrial membrane associated PARL into 54-kDa which
is regulated by the recently illustrated SPY complex 9. This new form of PINK1 is degraded by proteases within the
mitochondria in order to keep the PINK1 concentration in check.

In unhealthy
mitochondria, upon the loss of mitochondrial membrane potential that can be
induced artificially by mitochondrial uncouplers (e.g. carbonyl cyanide
m-chlorophenylhydrazone (CCCP)), PINK1 gets stabilised and activated on the
outer mitochondrial membrane (OMM) by processes which are not yet fully
discussed 10,11. Depolarised mitochondria then recruits cytosolic Parkin with
the help of enzymatic activity of PINK1 12. Parkin exists in a native auto-inhibited
conformation which becomes activated on mitochondrial depolarisation 13. Activated
PINK1 phosphorylates both Ubiquitin and Parkin at their respective Ser65
residues 14-17. Detailed structural and biophysical characterisation by
sovereign laboratories illustrated that phospho-ubiquitin (pUb) binds with high
affinity to phosphorylated Parkin. This binding allosterically induce conformational
changes that promote recruitment of its E3 ubiquitin ligase, and initiation of
Parkin activity 13–17. Active Parkin is proclaimed to ubiquitylate infinite
proteins that reside in the OMM, by elongating pre-existing ubiquitin chains attached
to OMM proteins or by ubiquitylating proteins de novo. Some of these proteins
include Mfn1/Mfn2 17. The ubiquitylation of mitochondrial surface
proteins recruits mitophagy initiation factors. Parkin
promotes ubiquitin chain linkages on both K63 and K48. K48 ubiquitination
initiates degradation of the proteins, and could allow for passive
mitochondrial degradation. K63 ubiquitination is thought to recruit autophagy
adaptors LC3/GABARAP which will then lead to mitophagy. It is still unclear
which proteins are necessary and sufficient for mitophagy, and how these
proteins, once ubiquitylated, initiate mitophagy.

PINK1 and Parkin independent mitophagy

The first such
mechanism characterised was NIX-dependent mitophagy, NIX and its regulator
BNIP3 are induced by hypoxia, bring about autophagy and have functions related
to apoptosis. They act as autophagy receptors by localising to the outer
mitochondrial membrane and contain LC3-interation motifs (LIR). Upon activation,
BNIP3 and NIX trigger opening of the mitochondrial permeability transition pore
(mPTP), depolarisation and recruitment of LC3/GABAR- APs for autophagosome
formation. NIX has proven to be vital for mitochondrial elimination during erythrocyte
maturation. Despite the fact NIX has been involved in the mitochondrial
translocation of Parkin, cross talk between NIX/BNIP3 and PINK1-Parkin mitophagy
pathways still remains unclear 18.

Conclusion and perspectives

 

Autophagic elimination of
mitochondria in mitochondrial biogenesis, regulates the changes in steady-state
mitochondrial number that are required to satisfy metabolic demand. Removal of
damaged mitochondria also maintains mitochondrial quality control. Mitophagy involves
distinct steps to recognize damaged organelles and to target them to autophagosome.
In mammals, NIX mediated mitochondria removal plays an important role during
erythropoiesis, and parkin and PINK1 can regulate the selective autophagy of
damaged mitochondria in many cell types. More precise and quantitative assays of
mitophagy are needed in all these systems. A more quantitative assessment of
mitophagy is needed to determine whether endogenous parkin mediates an increase
in the mitochondrial turnover rate. The study of mitophagy in animal models in vivo is also needed to rigorously test
the model that parkin and PINK1 mediate mitochondrial quality control. It remains unclear whether mitochondrial depolarization is the true
physiological trigger of PINK1–Parkin pathway induction, also how
accumulation of misfolded proteins in the mitochondrial matrix is sensed by
PINK1 to induce PARK2/ Parkin-mediated mitophagy of polarized mitochondria 19. Parkin has also been found to be a
tumour suppressor, suggesting it will be worth exploring the role of mitophagy
in cancer biology. The proposal that defects in mitophagy may be linked to
Parkinson’s disease suggests that this nascent research topic will also be important
to understand and, hopefully, to treat human disease.