Biomedical Engineering Reference
In-Depth Information
5. Mitophagy
and Disease
The efficiency of mitophagy may play a critical role in ageing and
the pathogenesis of various diseases (Fig.
1
).
5.1. Mitophagy
and Ageing
Mitophagy is proposed as being beneficial in postponing aspects
of ageing. As indicated above, in order to maintain healthy cells,
ROS-damaged mitochondria must be eliminated. However, as
autophagic (and mitophagic) activity declines with age, the effi-
ciency of removal of damaged mitochondria declines and promi-
nent symptoms of ageing become apparent, such as the
accumulation of damaged proteins, lipids, and organelles (
25, 39,
47, 48
).
A restricted food supply (incipient starvation) enhances
autophagy in experimental animals, and may partly explain why
caloric restriction retards the ageing process. Theoretically, it
might be able to offset the natural age-related decline of autophagy
and so prolong its essential housekeeping function in cells.
Therefore, achieving proper and sufficient function of autophagy
makes the manipulation of autophagy a prospect for slowing age-
ing in mammals and enhancing longevity (
4
).
5.2. Mitophagy
and Liver Disease
Under pathophysiological conditions, a significant change in
autophagic removal of mitochondria (and other cellular constitu-
ents) can occur. Evidence of enhanced levels of mitophagy are
found in liver biopsies of patients with Reye's syndrome (where
the disease causes fatty liver with minimal inflammation) (
49
) and
also is observed in a murine disease model using influenza B virus
(
50, 51
). Changes in the autophagic breakdown of mitochondria
can contribute to disease pathology (
51
). For example,
ATG7
-
deficient mice accumulate excessive numbers of peroxisomes,
deformed mitochondria, and concentric membranous structures,
in addition to ubiquitin-positive aggregates, in hepatocytes (
52
),
which can be anticipated to cause liver dysfunction in the long
run (
51
). The precise role of mitophagy in liver injury and poten-
tial for its modulation in liver cancer therapy remain to be explored
in detail.
5.3. Defective
Clearance
of Mitochondria
in Reticulocytes
Results in Hemolytic
Anemia
During terminal differentiation, erythroid cells undergo enucle-
ation to become reticulocytes. Subsequently coordinated removal
of organelles such as mitochondria occurs leading to the formation
of mature red blood cells (RBCs) (
53, 54
). Nix, a BH3-only mem-
ber of the Bcl-2 family (also known as Bnip3), is up-regulated in
erythroid cells undergoing terminal differentiation and is required
for dissipation of mitochondrial membrane potential (
54
). RBCs
from Nix
−/−
mice show abnormal retention of mitochondria (
55
).
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