Biology Reference
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these findings support the view that HtrA2 and parkin are both acting as
downstream effectors of PINK1 but in parallel pathways suggesting the PINK1
pathway bifurcates.
The contribution of HtrA2 to PINK1 pathology remains to be deter-
mined but it will be interesting to understand how this pathway is triggered and
how its activation leads to protection from mitochondrial stress. The p38 SAPK
pathway is known to be triggered by reactive oxygen species (ROS), which are
produced when mitochondrial electron transport is perturbed (Bradham and
McClay, 2006). It is possible that the PDZ domain of HtrA2 acts as a sensor
for unfolded proteins, and once activated by p38, HtrA2 may cleave unfolded
proteins and/or elicit a response to clear the damaged proteins, analogous to
bacterial DegS (Vaux and Silke, 2003). Loss of such a mechanism would have
important implications in conditions of mitochondrial dysfunction whether by
PINK1
mutation or by another insult.
V. FUNCTION OF THE PINK1/PARKIN PATHWAY
A recent wave of reports has begun to reveal new insights into the process in
which PINK1 and parkin normally function, and how their dysfunction may lead
to neuronal death (reviewed by Whitworth and Pallanck, 2009). These findings
indicate an important function of the PINK1/parkin pathway is to regulate the
interaction of mitochondria, help segregate damaged or dysfunctional units, and
promote their degradation by autophagy. This process likely acts as part of a
quality control mechanism to recognize terminally damaged mitochondria and
safely degrade them to prevent increased ROS production when senescent, and
potentially catastrophic rupture and release of proapoptotic factors.
Perhaps, the most significant clue into the mechanism by which PINK1
and parkin influence mitochondrial integrity came from analysis of the Drosoph-
ila models which showed that mutations in
grossly affect
mitochondrial morphology. Although mitochondria are often depicted as static
kidney bean shaped organelles, mitochondria are highly motile and interact with
one another to form interconnected tubular networks. These dynamic networks
undergo continual cycles of fission and fusion controlled by evolutionarily con-
served fission- and fusion-promoting factors (Chen and Chan, 2009). Among the
known mitochondrial fission- and fusion-promoting factors are the large dyna-
min-related GTPases dynamin-related protein 1 (Drp1), optic atrophy 1 (Opa1),
and mitofusin (Mfn) (Chen and Chan, 2009). Drp1 is a cytosolic factor that
assembles with mitochondria to promote mitochondrial fission, whereas Opa1
and Mfn reside in the inner and outer mitochondrial membranes, respectively,
where they act to promote mitochondrial fusion (Chen and Chan, 2009). Given
that mutations in
PINK1
or
parkin
PINK1
and
parkin
exhibit aberrant mitochondrial morphology,
