Mitophagy and Mitoptosis in Disease Processes - Protein Misfolding and Cellular Stress in Disease and Aging - page 94

in Caenorhabditis elegans ( 19 ) and the formation of synapses and
dendritic spines in rat neurons ( 20 ).
As a consequence of their roles in maintenance of the mito-
chondrial network, fusion and fission can serve to limit the extent of
mitochondrial damage generated at the organelle level and play a
key role in cell death ( 17 ). Fusion serves to mix and unify the mito-
chondrial compartment, an activity that is thought to constitute a
defense mechanism against ageing. As mtDNA is directly located at
the site of ROS production, it is particularly vulnerable to ROS-
mediated mutations. These mutations accumulate with age until a
bioenergetic threshold is breached, resulting in mitochondrial dys-
function that eventually leads to age-associated pathology and death
( 21 ). It is proposed that free mixing of mitochondrial genetic com-
ponents throughout the mitochondrial network protects mamma-
lian mitochondria from direct expression of respiration or other
defects caused by accumulated mtDNA mutations ( 22 ).
Given the importance of mitochondrial function, it is clear
that the rates of fusion and fission must be tightly controlled and
balanced, in response to a cohort of intra- and extracellular sig-
nals. A disturbance in the balance can lead to a variety of diseases
such as Autosomal Dominant Optic Atrophy (a common form of
inherited childhood blindness caused by defects in the OPA1 gene
whose product acts to maintain mitochondrial membrane mor-
phology) ( 23 ) and Charcot-Marie-Tooth disease subtype 2A
(mutations in the MFN2 gene, whose product is a mediator of
mitochondrial fusion, lead to a neurodegenerative disorder clini-
cally characterised by the gradual degeneration of peripheral neu-
rons) ( 24 ) (Fig. 1 ).
Several studies have indicated that mitochondrial morphol-
ogy changes during apoptosis, resulting in small, rounded, and
more numerous organelles. This extensive fission occurs before
caspase activation, which causes the ultimate demise of the cell.
Inhibition of the mitochondrial fission machinery inhibits cell
death, indicating its importance in apoptosis ( 25 ). Severe damage
of mitochondria or impaired fusion can lead to increased frag-
mentation of mitochondria, which are then selectively removed
by an autophagic process, termed mitophagy (see below) ( 26 ),
and which prevents the release of pro-apoptotic proteins from
damaged mitochondria. Therefore, apoptosis can be suppressed
upon induction of autophagy ( 27 ).

4. Mitophagy:
Mitochondrial
Turnover by
Autophagy

Mitophagy denotes the (selective) autophagic sequestration, and
subsequent degradation, of mitochondria ( 26, 28, 29 ). The com-
ponent amino acids and other basic building blocks are recovered