Biology Reference
In-Depth Information
Drosophila
PINK1
mutants was a characterizationof Drosophila
rhomboid-7
mutants
(McQuibban
et al.
, 2006), which shared remarkable phenotypic similarity with
PINK1/parkin
mutants, including muscle degeneration, locomotor deficits, male
sterility, and mitochondrial pathology. Intriguingly, rhomboid-7 and its homologs
are the only known mitochondrially targeted rhomboids, provoking the hypothesis
that rhomboid-7may cleave PINK1 in themitochondrion. Hence, it was exciting to
see that in Drosophila
mutants PINK1 is found almost exclusively in the
full-length form, suggesting that rhomboid-7maywell be the protease responsible for
PINK1 cleavage (Whitworth
rhomboid-7
et al.
,2008). Additional experiments revealed that
rhomboid-7
genetically interacted with
PINK1
and
parkin
, in a pattern consistent
with it acting upstream of
PINK1
(Whitworth
et al.
, 2008). While coexpression of
rhomboid-7
with
PINK1
or
parkin
caused a synergistically enhanced rough eye
phenotype, the
rhomboid-7
overexpression rough eye could be significantly sup-
pressed by removal of
PINK1
but not vice versa (Whitworth
et al.
, 2008). Interest-
ingly, it was also shown in this study that
rhomboid-7
genetically interactswith
HtrA2
and contributes to the generation of one of the cleaved forms of HtrA2.
The cleavage of PINK1 provides a potential mechanism to release it
from mitochondria and activate the recruitment of parkin. As mentioned above,
it was suggested that PINK1 may directly phosphorylate parkin to stimulate its
translocation (Kim
et al.
, 2008b) but this has been disputed by others (Vives-
Bauza
, 2010). More recently, others have described that the processed form
of PINK1 is rapidly degraded by the proteasome, and furthermore suggested the
cleavage may be a mechanism to constitutively remove PINK1 from healthy
mitochondria inactivating the signal and preventing parkin recruitment
(Narendra
et al.
, 2010). This inference comes principally from compelling
evidence that full-length PINK1 is stabilized upon mitochondrial toxification,
a condition which stimulates parkin recruitment. In contrast, this study suggests
that the mammalian homolog of rhomboid-7, PARL, does not contribute to the
cleavage of mammalian PINK1; however, the data for this are rather weak and
inconclusive and are disputed by others (Deas, Plun-Favreau, and Wood, per-
sonal communication). Nevertheless, the model that stabilization of full-length
PINK1 is the active form that recruits parkin is in complete contradiction to the
genetic interactions of
et al.
. While the mechanism
that regulates PINK1 activity remains to be resolved, it seems certain that some
as yet known signal activates PINK1 to stimulate the recruitment of parkin to
dysfunctional mitochondria.
Recent work has also advanced our understanding of how parkin-
mediated ubiquitination may affect mitophagy. Ubiquitination of the outer
mitochondrial surface is thought to promote mitophagy by acting as a recruit-
ment signal of the adaptor molecule p62/SQSTM1 which directly interacts with
both ubiquitin on the degradation substrate and LC3 on the nascent autophagic
membrane (Kirkin
rhomboid-7
with
PINK1
and
parkin
et al.
, 2009). Hence, elucidating the identity of parkin
