Biology Reference
In-Depth Information
several laboratories tested the hypothesis that PINK1 and parkin regulate mito-
chondrial morphology. These studies revealed that removing a single copy of the
fission-promoting factor
Drp1
in
PINK1
or
parkin
mutants dramatically reduces
their viability. In contrast,
PINK1
and
parkin
mutant phenotypes are suppressed
by overexpressing
to enhance mitochondrial fission, or by introducing loss-
of-function mutations in genes encoding the fusion-promoting factors
Drp1
Opa1
and
Mfn
, 2008).
Together, these findings suggested that the PINK1/parkin pathway promotes
mitochondrial fission and/or inhibits mitochondrial fusion. Indeed, these same
conclusions were drawn from a largely overlooked work by Riparbelli and
Callaini (2007) which described detailed analysis of the spermatogenesis defect
in
(Deng
et al.
, 2008; Park
et al.
, 2009; Poole
et al.
, 2008; Yang
et al.
mutants. This study found that the failure of spermatids to individualize
is preceded by a defect in the remodeling of the specialized mitochondrial
derivative, the Nebenkern, which fails to divide into the normal major and
minor derivatives, thus appearing like excess fusion or aberrant fission. Admit-
tedly, because of the specialized nature of spermatogenesis it cannot be assumed
parkin
a
priori
that the same mechanism would be shared in the neuromuscular tissues;
however, the subsequent studies validate these early observations.
Various conditions, however, indicate that PINK1 and parkin are not
obligatory components of the mitochondrial morphogenesis machinery. For ex-
ample, mutations in core components of the fission/fusion machinery such as
Drp1
in various organisms have much more severe phenotypes
than that exhibited by loss of
,
Opa1
, and
Mfn1/2
PINK1
or
parkin
(Chen
et al.
, 2007; Frezza
et al.
,
2006; McQuibban
, 2005). More likely, these factors
regulate the mitochondrial morphogenesis machinery only in a specific biological
context. Some recent findings have suggested possible mechanisms by which
derangements in mitochondrial fission could impact tissue viability. Genetic
studies of Drosophila
et al.
, 2006; Verstreken
et al.
showed that loss-of-function mutations result in a
failure to efficiently traffic mitochondria to presynaptic terminals in neurons,
which in turn impairs calcium buffering and synaptic transmission (Verstreken
et al.
Drp1
, 2005). While these findings are consistent with some of the phenotypes
documented in
-deficient flies and mice, the distribution of
mitochondria in motor neurons appears to be unaffected in
PINK1
and
parkin
PINK1
-deficient flies
(Morais
, 2009), and a mitochondrial trafficking defect does not readily
account for the flight muscle and male germline defects of
et al.
parkin-
deficient flies, or the selective vulnerability of DA neurons to loss of PINK1 and
parkin activity. However, another recent study has provided evidence that PINK1
may interact with the mitochondrial trafficking machinery, Miro and Milton
(Weihofen
PINK1
and
, 2008), so further investigation into this mechanism is warranted.
Another mechanism by which defective mitochondrial fission could
impact tissue viability derives from a recent study involving live-cell imaging
of mitochondrial dynamics in cultured vertebrate cells (Twig
et al.
et al.
, 2008a,b).
