Mitophagy and Mitoptosis in Disease Processes - Protein Misfolding and Cellular Stress in Disease and Aging - page 99

The loading and unloading of oxygen can induce oxidative stress
in RBCs ( 56 ). As already discussed, mitochondria are a major site
for the generation of ROS, therefore, the retention of mitochon-
dria in RBCs would be expected to be deleterious. Indeed, Nix −/−
RBCs are reported to produce more ROS, display increased
caspase activation in vitro and undergo faster turnover in vivo
( 55 ). Thus, successful degradation of mitochondria in Nix +/+
RBCs will prevent mitochondria-dependent caspase activation
and subsequent cell death, reduce ROS production and sustain
the survival of erythrocytes. Interestingly, Nix deficiency does not
affect the formation of autophagosomes in reticulocytes, instead,
mitochondria are clustered outside of autophagosomes ( 55 ).

6. Mitoptosis:
The Elimination
of Mitochondria

Mitoptosis can be defined as a type of mitochondrial elimination
( 57 ). In 1992, Tedesci and colleagues suggested that mitochon-
dria possess a mechanism of self-elimination ( 58 ). This function
was ascribed to the MPT, and was not envisaged as requiring any
extramitochondrial proteins. Rather, it was conceived as being
initiated by a signal originating from a particular mitochondrion,
such as ROS production. This is why one can consider the out-
come as the programmed destruction of the mitochondrion
(mitochondrial suicide). For this event, Skulachev coined the
word “mitoptosis,” by analogy with apoptosis, programmed
death of the cell ( 59, 60 ) (Fig. 1 ).
It has been proposed that mitoptosis represents a mechanism
by which mitochondria undergo extensive fragmentation and
subsequent caspase-independent elimination during apoptosis
( 61 ). On the other hand, apoptotic stimuli target mitochondria
for degradation by autophagy, as fragmented mitochondria are
found within autophagosomes ( 62 ). Recently, in lymphoblastoid
T cells, two types of mitoptosis have been described: OMM and
IMM. During OMM mitoptosis, swelling, condensation, and the
collapse of IMM cristae precede disruption of the OMM, follow-
ing which the swollen cristae remnants distribute throughout the
cell cytoplasm. By contrast, IMM mitoptosis appears to be char-
acterised by the coalescence of mitochondria, loss of density of
the matrix and subsequent rupture of IMM cristae, while the
OMM remains unchanged ( 57 ).
In highly glycolytic human cervical carcinoma (HeLa) cells, a
novel and apparently more robust, multi-step (non-autophagic)
mitoptotic process has been described. The sequence of events is
as follows: (1) fission of mitochondria, (2) clustering of the frag-
mented mitochondria in the perinuclear region, (3) sequestration

6.1. Initial Conception
and Characterisation