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as a whole, or oxidized mitochondrial proteins might be degraded by a mito-
chondrial proteolytic enzyme.
As previously mentioned, the process of the degradation of mitochondria
as a whole is called mitophagy. Mitochondria should be recognized by macro-
phagy mechanism and are degraded in the lysosomes. The signal for this seems
to be the loss of mitochondrial membrane potential rather than the presence
of oxidized protein moieties. It seems to be reasonable to believe that an
oxidative damage of mitochondria might also lead to a loss of the membrane
potential and induce the recognition cascade. Recently, it was shown that
parkin translocates to mitochondria during oxidative stress (399). For parkin
translocation, a functional PINK1 is required. Parkin (an E3 ligase enzyme)
catalyzes the polyubiquitination of VDAC1 and an autopolyubiquitination via
Lys27 and Lys63 (408). Afterward, the autophagic protein p62/SQSTM1/
sequestosome-1 is bound to mitochondria and mitophagy starts. Whether there
are additional proteins involved, as well as the nature of the E2 ubiquitin-
conjugating enzyme are still under investigation.
However, it seems to be an inefficient way to maintain mitochondrial
homeostasis via the degradation of whole parts of the mitochondrial network
after fission events. More effective is the targeted degradation of unwanted or
damaged proteins, maintaining, therefore, the protein pool within mitochon-
dria. Mitochondria contain a set of proteases in different compartments,
including the Lon protease in the mitochondrial matrix (409).
The Lon protease was found to be of special importance for the degradation
of oxidized mitochondrial proteins. The Lon protease received its name from
the E. coli lon mutants. These mutants form long undivided filaments upon
UV irradiation (410-412). Studies demonstrated that Lon degrades abnormal
and damaged proteins and short-lived regulatory proteins. Lon is expressed in
the cytosol of prokaryotes and in the mitochondria and peroxisomes of eukary-
otes (411, 413-417). Lon is composed of identical subunits; each of them
carry the ATPase and protease domains. In total, each Lon subunit has several
domains—the amino-terminal (N) domain that binds protein substrates, the
ATPase (AAA) domain important for ATP-binding and hydrolysis, and finally
the carboxyl-terminal (P) domain with the proteolytic active site (418). All
these subunits are in close communication during the catalytic process and it
seems that the coordination of ATP hydrolysis and proteolytic degradation is
required for catalytic activity of Lon. Lon is a member of the AAA family
of ATPases ( A TPases A ssociated with a variety of cellular A ctivities). All
AAAases have a conserved ATP-binding module of
200 amino acids that
assembles into oligomeric rings. Also Lon is a homooligomeric and ring-
shaped complex. Several studies revealed that Lon is a hexameric structure in
prokaryotes (419, 420), whereas it is heptameric in yeast (421).
Although mitochondrially located, the Lon protease is a nuclear encoded
enzyme and has, therefore, to be transported into the mitochondria. In mam-
malian cells, Lon is upregulated in stress response (416, 422, 423). The k.o.
or downregulation of eukaryotic Lon results in several cellular metabolic
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