Mitophagy and Mitoptosis in Disease Processes - Protein Misfolding and Cellular Stress in Disease and Aging - page 92

circular mitochondrial genome and numerous mitochondrial
ribosomes. Mitochondria synthesise only a small number of
(mostly respiratory chain) proteins; 90% of the mitochondrial
protein mass is encoded by the nuclear genome, synthesised in
the cytosol and imported into mitochondria. Thus, mitochon-
drial biogenesis requires the co-ordination of gene expression
from mitochondrial and nuclear genomes ( 1-4 ).
Mitochondria have a significant role in determining the bioener-
getic status of cells as they are the site of oxidative phosphoryla-
tion, whereby the ATP synthase complex generates ATP coupled
to electron transfer from respiratory substrates to oxygen by a
series of oxidation-reduction reactions and the pumping of pro-
tons across the IMM from the matrix space ( 1, 2 ). A significant
consequence of this activity is the production of reactive oxygen
species (ROS); the levels produced can impact negatively not only
on mitochondrial function, but more broadly on cellular function
(see below).
Mitochondria are also home to key biosynthetic pathways
(e.g. heme and lipid synthesis), and participate in the regulation
of cellular Ca 2+ levels. Programmed cell death (apoptosis) can
involve mitochondrial events and crucial cell death regulators
such as Bcl-2 are associated with mitochondria ( 1, 2 ).

2.2. Mitochondrial
Dysfunction: Defects
in Protein Quality
Control Systems,
Mitochondrial
or Nuclear DNA
Mutations,
and Changes
in Mitochondrial
Morphology

A highly conserved, intra-organellar, proteolytic process conducts
protein quality control (PQC) within mitochondria ( 4 ) by moni-
toring the folding and assembly of mitochondrial proteins and
selectively removing non-assembled, misfolded, damaged and
excess proteins from the organelle. Components of this system
include a proteasome degradation pathway (located in the OMM),
molecular chaperones, and energy-dependent proteases (confined
mostly to the IMM and matrix) ( 4, 5 ). Once recognised, target
proteins are degraded to peptides, and subsequently either
exported from mitochondria or degraded further to amino acids
by various oligopeptidases ( 5 ). As a consequence of their function
in PQC, matrix proteases directly impact on the biogenesis of the
respiratory chain complexes and ATP synthase. Mutations in
genes encoding components of the mitochondrial PQC system
are linked to a number of ageing-related neurodegenerative dis-
eases ( 5, 6 ) (Fig. 1 ). For example, mutations in a subunit of the
m -AAA protease, paraplegin, cause an autosomal recessive form
of Hereditary Spastic Paraplegia (HSP). Accordingly, mitochon-
drial dysfunction and axonal degeneration in the absence of para-
plegin may result from the accumulation of non-degraded,
misfolded IMM proteins or impaired regulatory steps during
mitochondrial biogenesis, or both. Interestingly, mutations
affecting expression of the mitochondrial chaperone HSP60,
which is localised to the matrix, cause an autosomal dominant
form of HSP ( 5 ).