Biology Reference
In-Depth Information
Compromised mitos
Fusion
Identify damaged
components/units
Network period
Damaged mitos:
- PINK1 signals
- Parkin recruited
Fission
Healthy mitochondria
Mito segragated
Autophagy
Solitary period
Mfn ubiquitinated,
prevents refusion
Healthy mitos:
Recover membrane
potential
Figure 1.2. Proposed function of PINK1 and parkin in regulating the segregation of damaged
mitochondria. Mitochondrial fusion provides a mechanism for partially damaged (com-
promised) mitochondria to mix their contents with healthy mitochondria and allow
complementation of dysfunctional components (proteins, lipids, and mtDNA).
Subsequent fission can generate a daughter mitochondrion that has accumulated a
significant degree of damage such that complementation would be insufficient, and
must be degraded to avoid potentially catastrophic rupture. An unknown mechanism
stimulates PINK1 to signal to the recruitment of parkin to that mitochondrion. Parkin
ubiquitinates Mfn, which prevents refusion and segregates that mitochondrion for
subsequent autophagy.
mitochondrion is detected, perhaps by an unidentified internal mechanism, and
stimulates PINK1 to promote the recruitment of parkin. parkin translocates to
that mitochondrion where it ubiquitinates Mfn. The initial effect of parkin
monoubiquitination of Mfn may be to interfere with mitochondria tethering
and exclude damaged mitochondria from rejoining the mitochondria network.
Subsequently, p62/SQSTM1 may recognize multiubiquitinated Mfn or VDAC1
on these mitochondria and recruit autophagosomes. In this way, mitochondria
that have acquired an unsustainable amount of damage, for example, through
prolonged exposure to oxidative stress, are sequestered and safely destroyed, and
a healthy mitochondrial network is maintained.
