Protein Misfolding and Cellular Stress: An Overview - Protein Misfolding and Cellular Stress in Disease and Aging - page 9

In conclusion, ER contains a unique set of chaperones,
including lectins, which in the young and healthy cell can cope
with newly imported and damaged proteins generated after
“mild” stress. However, in case of “severe” stress a number of
misfolded protein sensors in concert induce a range of protective
genes, including folding chaperones as well as genes coding for
antioxidants. At the same time, signals initiating apoptosis are
activated, and the balance between restoration and cell death
depends on the severity and duration of the insult.

4. Mitochondrial
Protein Quality
Control, Unfolded
Protein Response
and Oxidative
Stress

Mitochondria contain proteins coded from at least a thousand
different genes ( 41, 42 ), nearly all of which are nuclear encoded
and contain a leader sequence used for targeting to the mito-
chondrial import machinery ( 43 ). In addition, 22 tRNAs, two
ribosomal RNAs as well as 13 components of the respiratory
chain are coded from the mitochondrial DNA (mtDNA),
which is a reminiscence from the aerobic protobacteria which
invaded pre-eukaryotic cells more than a billion years ago.
Eukaryotic mitochondria are formed by an outer membrane
(OM), an inter-membrane space (IMS), inner membrane (IM),
and a matrix (M). Relevant for the presence context is that
most of the metabolic activity takes place in the matrix, and
the production of energy-rich ATP as a result of the respira-
tory chain activity, is associated with IM and IMS (see also
Chap. 6) and ( 16 ).
Although it may not be correct to talk about numbers, since
there is a dynamic balance between small distinct and large reticu-
lum formed mitochondria, the “number” of active units varies
drastically, depending on the metabolic activity needed ( 44 ).
Especially muscle, heart, and brain cells that are highly metaboli-
cally active may contain several hundred active units, each con-
taining many mtDNAs. This large number and the dynamic
nature of the mitochondria network make the cell robust to
insults, such as oxidative stress. This will be discussed in details
below; suffice here to say that “mildly” damaged mitochondrial
units can fuse and be repaired by “healthy” ones, and that
“severely” dysfunctional units may be removed without immedi-
ate serious consequences for the survival of the cell ( 44, 45 ).
Before discussing this and other consequences of mitochondrial
stress, it is appropriate shortly to recapitulate the current knowl-
edge about protein folding and misfolding inside mitochondria as
well as the stress response through the mitochondrial unfolded
protein response (mtUPR).