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substrates has come under intense scrutiny. Two proteins localized to the mito-
chondrial outer surface have recently been reported as putative parkin substrates,
mammalian VDAC1 and Drosophila Mfn (Geisler
et al.
, 2010; Poole
et al.
, 2010;
Ziviani
, 2010). While the modification of the abundant protein VDAC1
would provide a robust signal for autophagosome recruitment, the ubiquitination
of Mfn is a particularly exciting target due to its role in mitochondrial fusion. As
discussed above, dysfunctional mitochondria destined for destruction appear to
be sequestered from the rest of the healthy network prior to engulfment (Twig
et al.
et al.
, 2008a), but it is unclear how such a mechanism works.
Interestingly, instead of observing a “smear” of polyubiquitin adducts
Mfn was modified as two distinct ubiquitinated forms which likely correspond to
mono- and multiubiquitinated Mfn. A number of hypotheses have been pro-
posed as to how this modification may be crucial to regulated mitophagy (Ziviani
and Whitworth, 2010). The first proposes that ubiquitinated Mfn may be de-
graded by the proteasome, thus removing the profusion factor from the outer
surface in a process similar to the removal of misfolded proteins from the
endoplasmic reticulum (a process known as Endoplasmic Reticulum-Associated
Protein Degradation [ERAD]). A similar mechanism could remove ubiquitinated
Mfn specifically from damaged mitochondria and reduce their refusion capacity.
However, monoubiquitination does not typically lead to degradation. The ubi-
quitinated protein may develop new characteristics that affect its activity,
subcellular localization, or its interaction with other proteins. Indeed, mono-
ubiquitination is becoming recognized as an important regulatory mechanism in
controlling protein activity and signaling. A second hypothesis proposes that
Mfn ubiquitination might physically interfere with the formation of
Mfn
dimers and prevent mitochondria tethering. This process is required for fusion,
and its abrogation would thus preclude refusion of damaged mitochondria.
Regardless of the mechanism, these findings provide a molecular expla-
nation for the previously reported genetic interactions; briefly, genetic perturba-
tions that promote mitochondrial fragmentation suppress
trans
PINK1/parkin
mutant
phenotypes. Consistent with this, loss of
parkin
or
PINK1
leads to an increased
abundance of Mfn and hyperfused mitochondria (Poole
, 2010). While it
remains to be shown that mammalian parkin acts in an analogous fashion to
regulate mitophagy, some reports indicate this may be likely (Tanaka and Youle,
personal communication). As Drosophila Mfn is the sole ubiquitously expressed
Mitofusin homolog and likely performs functions of both mammalian Mfn1 and
Mfn2, it will be interesting to determine whether this mechanism may be
preferentially mediated by Mfn1 or Mfn2.
In consideration of all the current data, the following mechanism by
which regulated fusion and fission of mitochondria may contribute to a quality
control process that recognizes and removes damaged mitochondria is proposed
(Fig. 1.2). Following a fission event, a terminally damaged daughter
et al.
