Question

Describe mitochondrial pathways of stress in detail

Answer 1

Mitochondria are double-membrane organelles of which structure is characterized by containing lipid bilayers in almost eukaryotic cells. Mitochondria are composed of approximately 1100 proteins, which are encoded by genes located in both the mitochondrial genomes (mtDNA) and the nuclear genomes. Yet, most of the mitochondrial proteomes are encoded by the nuclear genomes, synthesized in the cytosol and imported into mitochon-

dria. Mitochondria possess their own genome, which encodes 13

polypeptides of the electron transport chain (ETC), 22 tRNAs and

2 rRNAs required for their synthesis. Organismal lives in a sophis-

ticated and unstable environment, and different adverse environ-

mental conditions can induce varying degrees of mitochondrial

stress. Different mitochondrial stress may cause mitochondrial

dysfunction in different degrees.

Communication between Mitochondria and Nucleus :-

In order to quickly adapt to changeable conditions, mitochon-
dria evolve to well-integrated organelles communicated with other
cell compartments. Under stress conditions, the signal conduction
can be achieved from the misfolded or unfolded mitochondrial
proteins within the matrix to the nucleus. Mitochondrial retro-
grade signaling or mitochondrion to nucleus communication has
been discovered by Butow and Avadhani laboratories. Mainte-
nance of protein homeostasis, the mitochondrial retrograde
response increases nucleus encoded mitochondrial proteases and
chaperones synthesis to facilitate protein folding or clearance of
defective proteins in response to decreased mitochondrial activity,
which is essential for organism functionality and survival.
Recent works have not completely defined UPRmt extensively in
mammals, but two potential signal transduction pathways may
involve in retrograde response. One is mitochondrial membrane
potential. The retrograde response can be triggered by low mem-
brane potential, and blocked via restoring the membrane potential
in rho and cox4 null yeast.The other one is cytosolic calcium
accumulation. Assembling calcium within cytosolic causes activa-
tion of calcineurin and subsequently transcription factors. Under
accumulation of misfolded or unfold proteins conditions, protein
kinase R (PKR) is activated and elevates levels of phosphorylated-
JNK9
, which promotes the transcription factor c-Jun bind to the
activation protein-1 (AP-1) element, then activates the transcrip-
tion of CHOP.10,11 There exist two mitochondrial unfolded protein
response elements (MURE1 and MURE2) adjacent to CHOP bindingsite which present in promoters of UPRmt responsive genes.
Interestingly, activation of UPRmt via JNK/c-jun pathway requires
ClpP protease that could be a potential factor for inducing the
UPRmt.
During mitochondrial stress, cytosolic calcium homeosta-
sis disruption activates the transcription factors of C/EBP homolo-
gous protein (CHOP), extracellular signal-regulated kinase 1
(ERK1), and nuclear factor kappa B (NF-jB).6 NF-jB activation is
independently of the traditional repressor IjBa, but dependent
on the inhibitor IjBb dephosphorylation, inducing NF-jB outward
from the cytoplasm to the nucleus.Activation of these transcrip-
tion factors turn on the expression of UPRmt target genes, including
the mitochondrial chaperones HSP60, HSP10 and mtDnaJ encoded
by the nuclear genome.Furthermore, upon mitochondrial stress
additional proteases ClpP, Yme1L1, Lon and PMPCB, the import
component TIMM17A and the enzymes NDUFB2, endonuclease G
and thioredoxin 2 are all upregulated.
There contain two particular mitochondrial chaperone systems
that boost the newly synthesized or imported proteins folding in
the matrix. mtHSP70, part of presequence translocase associated
import-motor (PAM) complex, and polymer HSP60/HSP10 (chaper-
onin60/10) as main machinery, which is evolutionary conserved to
restore mitochondrial proteostasis. HAF1 and UBL5/DVE-1 com-
plex are two main downstream effectors of UPRmt in mitochondrial
matrix. HAF1 acts as an ATP-binding cassette (ABC) peptide trans-
porter located in mitochondrial inner membrane, which is essential
for UPRmt signaling cascade. A small ubiquitin-like protein UBL5
and a transcription factor DVE-1 form a complex translocated into
the nucleus that regulate the transcriptional activation of HSP60.
Recent findings demonstrate a separate UPR other than the ‘classi-
cal’ UPRmt, which is independent on CHOP.21 The separate UPR is
performed in two steps in the mitochondrial IMS. First of all, the
26S proteasome degrade the ubiquitinated unfolded or misfolded
proteins. Then, the overloaded proteins are obliterated through
the protease HTRA2. Aggregation IMS proteins evoke estrogen
receptor a (ERa) via protein kinase B (AKT) phosphorylation.
ERa activation boosts the transcription of the nuclear respiratory
factor 1 (NRF1) and HTRA2 to maintain mitochondrial homeostasis.
Recently, we were not able to confirm certain signaling pathway of
UPRmt, even more signaling molecules should be identified.
Mitochondrial protein import efficiency :-
Recent studies indicate that the mitochondrial protein import
efficiency is a potentially valuable pathway to assess mitochon-
drial function. As a result of mitochondrial unique structure,
the protein import encounters enormous challenges. More than
99% of the total mitochondrial protein is synthesized in the cyto-
plasm which is encoded by the nuclear genome. The synthesized
protein traffic to mitochondria by signal sequences as precursors.
Import into mitochondria requires the translocase of the outer
mitochondrial membrane (TOM) and the inner mitochondrial
membrane (TIM).The outer mitochondrial membrane (TOM)
acts as entrance, then the translocase of the inner mitochondria
membrane (TIM) targets precursor proteins to mitochondria
lumen.Proteins translocated to the mitochondrial matrix have
an amphipathic helix, termed N-terminal mitochondrial targeting
sequence (MTS). Firstly, the MTS binds to the cytoplasm surface
of the mitochondria by the outer mitochondrial membrane chan-
nel, subsequently cross the inner membrane and enter the matrix
through the TIM23 complex. Once located in the matrix, with the
assistance of mitochondria chaperones system including HSP60
and mtHSP70, the MTS is cleaved in the promotion of protein
refolding or assembling in the mitochondria lumen.18
The activating Transcription Factor associated with Stress-1
(ATFS-1), which contains both nuclear localization sequence (NLS) in the leucine zipper domain and N-terminal MTS, serves
as a bridge between the mitochondria and nucleus in UPRmt signal-
ing, and senses the import efficiency of mitochondria. Under basal
condition, ATFS-1 is targeted to mitochondria and degraded by the
Lon protease as an invalid regulatory mechanism.Upon mito-
chondrial stress, UPRmt signaling impairs mitochondrial import
efficiency, part of ATFS-1 cannot be imported into mitochondria
and assembles in the cytoplasm. Due to the NLS of ATFS-1, it
can traffic to the nucleus to induce a protective transcriptional pro-
gram to relieve the damage of mitochondrial stress. TIM-17 and
TIM-23, two key elements of the TIM23 complex, are upregulated
by ATFS-1, which are essential for the N-terminal MTS proteins
imported to the mitochondrial matrix. As expected, ATFS-1 acti-
vated the expression of the mitochondrial chaperone and proteases
genes to restore import efficiency and re-establish mitochondrial
homeostasis. Recent findings have shown that any condition that
disturbs import efficiency, such as deletions in mitochondrial ETC
genes26, mitochondrial chaperone and protease inhibition12,23,
cause ATFS-1 dependent UPRmt. These studies demonstrate that
the UPRmt alters mitochondrial metabolism to protect mitochon-
drial homeostasis and cell survival during stress.
Conclusions :-
Complicated and changeable environment, and the external
stress can perturb mitochondrial function, cells evolve multiple
signaling pathways to adapt to protect mitochondria and maintain
cellular homeostasis. The molecular mechanisms of mitochondrial
stress signaling pathways are quite complex and have dual func-
tions in cell survival and death. The mitochondrial unfolded pro-
tein response has been described, but the explicit mechanisms
have only recently begun to be studied. Recent researches of the
mitochondrial unfolded protein response determine that the retro-
grade response and mitochondrial protein import efficiency act as
indicators of mitochondrial function. Here, we have depictive sev-
eral mitochondrial signaling pathways that protect mitochondrial
function and cell survival during mitochondrial stress. Meanwhile,
we review the UPRmt mechanism of transcriptional activation to
alleviate mitochondrial dysfunction during stress. Under mito-
chondrial stress, disruption or dysfunction of the mitochondria
has been associated with several pathological conditions, including
metabolic diseases, cancer and neurodegenerative diseases. In the
future, it will play a pivotal role in determining whether the signal-
ing pathways are protective against diseases during mitochondrial
dysfunction. These studies are still in the early stages. Further clar-
ification of the full complexity of the UPRmt pathway and its role in
physiology and pathology will be a major goal for years to come.