Protein Misfolding and Cellular Stress: An Overview - Protein Misfolding and Cellular Stress in Disease and Aging - page 11

partly elucidated the signal pathway. Upon unfolding stress, the
cytosolic DVE-1, which is homologous to the mammalian SATB1
and SATB2, relocate to the nucleus and interact with the
hsp60/10 promoter. Simultaneously, UBL-5, which is up-reg-
ulated during the unfolding stress, interacts with DVE-1, thus
possibly enhancing the stress response. Despite these results, the
stress signal(s) inside and from the mitochondria have not yet
been found. However, it seems that ClpP activity is necessary for
the response, since down-regulation of the expression of ClpP in
C. elegans alleviated the induction of DVE-1 and UBL-5. So,
proteolytic digestion of some mitochondrial proteins that are able
to sense the accumulation of misfolded proteins is probably
needed. It could be speculated that such proteins are normally
stabilized by chaperones, for example, hsp70, like PERK, IRA1,
and ATF6 in the ER. Upon loading with unfolded proteins,
hsp70 is released from the protein, leaving it exposed and subject
to degradation. It has been speculated that the degradation prod-
ucts constitute the active signalling substances or that the putative
effecter protein is a repressor of the stress response ( 7 ). But how
is the signal then transmitted to DVE-1? Whatever the exact
mechanism, the important point here is that the mitochondrion
is able to sense misfolded proteins and promote induction of pro-
tective chaperones and proteases. Interestingly, as mentioned,
CHOP, which is the same pro-apoptotic transcription factor as
activated in the ER stress pathway ( 22, 34 ), is also implicated in
the mtUPR ( 51, 54 ). However, in the case of mtUPR, CHOP is
activated through an AP-1 binding site, and probably through
the pro-apoptotic JNK pathway ( 54 ), whereas CHOP in the
erUPR is activated through the ER stress element (ERSE) binding
motive as well as through the PERK-ATF4 pathways ( 55 ). Thus,
like the erUPR, the mtUPR at the same time as giving signal to
inducing protective genes, also initiates cell death signals. Whether
these signals may take over must depend on both the duration
and severity of the stressor(s).
As discussed above, the stressors in the cytosol and in the ER
may be misfolded proteins, which through more or less eluci-
dated mechanisms, for example, fibril formation, Ca ++ redistribu-
tion, and proteasome inhibition, disturb the mitochondrial
function, giving rise to oxidative stress and cell injury, which is
combated by the various defense systems, and if not possible lead-
ing to cell death. Surprisingly, although the mentioned over-
expression of delta-OTC in COS cells induced expression of
chaperones and proteases, the effect on the respiratory chain and
the possible creation of oxidative stress was not investigated ( 51 ).
However, in experiments where a misfolding variant of the short-
chain acyl-CoA dehydrogenase (SCAD) protein was transiently
over-expressed in an astrocytic cell line we have observed distur-
bance of the mitochondria dynamics, probably due to oxidative