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This study showed that while many products of mitochondrial fission rapidly fuse
again with the mitochondrial network, a proportion of the fission products exhibit
a decreased membrane potential and a decreased probability of fusion. These
defective fission products are frequently targeted to the lysosome for degradation
through a process termed mitophagy (Twig
, 2008a). Autophagic turnover of
organelles is becoming recognized as another of the myriad cellular functions of
ubiquitin modification, and has been linked to the degradation of peroxisomes
(Kim
et al.
, 1999).
These findings raise the possibility that derangements in PINK1 and parkin could
impair the selective turnover of damaged and dysfunctional mitochondria.
Subsequent work has provided substantial support for this hypothesis by
showing that parkin is selectively recruited to damaged mitochondria upon
treatment of cultured cells with mitochondrial damaging agents, and that parkin
promotes the turnover of these damaged mitochondria (Narendra
et al.
, 2008a) and paternally delivered mitochondria (Sutovsky
et al.
, 2008).
Moreover, several studies have also shown that PINK1 is required for the
translocation and mitophagy-promoting activity of parkin, consistent with
their known genetic hierarchy, ultimately leading to mitochondrial ubiquitina-
tion and recruitment of the autophagy machinery (Geisler
et al.
et al.
, 2010; Kawajiri
et al.
, 2010).
Importantly, this mechanism is conserved in Drosophila further supporting it as a
major and important function of the pathway (Ziviani
, 2010; Matsuda
et al.
, 2010; Narendra
et al.
, 2010; Vives-Bauza
et al.
, 2010).
A couple of key questions arise from these studies; how is PINK1
regulated to stimulate the recruitment of parkin, and how does parkin-mediated
ubiquitination of mitochondria help segregate damaged mitochondria and stim-
ulate mitophagy? For the first question, surprisingly, little is still known about the
regulation of PINK1. It is generally recognized that PINK1 is rapidly imported
into the mitochondria where it has been found in several locations with some
part in the intermembrane space and some part on the outer surface (Silvestri
et al.
et al.
, 2008). It is also recognized that PINK1 exists in at least
two major forms: a full-length form and a processed form resulting from an N-
terminal cleavage (Silvestri
, 2005; Zhou
et al.
, 2005). The cleaved form has been proposed to
be exported to the cytoplasm where it is sufficient to exert a neuroprotective
function against mitochondrial toxins (Haque
et al.
, 2008). In another key
advance from the Drosophila models, the putative processing protease has been
proposed to be a member of the rhomboid intramembrane proteases.
Rhomboid proteases, named after the founding member the Drosophila
et al.
rhomboid
gene which is involved in EGF signaling, are an unusual family of proteases
that have a specialized function to catalyze a hydrolytic cleavage within the hydro-
phobic environment of transmembrane domains (Freeman, 2008, 2009). Although
not very numerous, the function of rhomboid proteases have been linked to a wide
variety of biological processes, including mitochondrial membrane remodeling
(Herlan
et al.
, 2003; McQuibban
et al.
,2003). Coincident with the description of
