Core Concepts
Activation of the mitochondrial unfolded protein response (UPRmt) regulates the dynamic formation and disassembly of stress granules (SGs) to maintain mitochondrial homeostasis under stress conditions.
Abstract
The content describes a novel crosstalk between the mitochondrial unfolded protein response (UPRmt) and the integrated stress response (ISR) involving stress granules (SGs).
Key highlights:
- Induction of UPRmt by mitochondrial stressors GTPP or paraquat leads to activation of the ISR, resulting in an initial and transient formation of SGs.
- The upregulation of GADD34 during late UPRmt protects cells from prolonged stress by impairing further assembly of eIF2α-dependent SGs.
- Mitochondrial respiration is enhanced when SGs are absent during UPRmt activation, suggesting that UPRmt-induced SGs have an adverse effect on mitochondrial homeostasis.
- UPRmt activation also impairs the assembly of eIF2α-independent SGs, potentially through upregulation of SG disassembly chaperones.
- The dynamic regulation of SG assembly and disassembly is an important component of the UPRmt response to maintain mitochondrial functions under stress conditions.
Stats
Approximately 25% of cells were positive for SGs at 2 h post GTPP treatment.
GTPP treatment resulted in a 2 to 3-fold increase in mRNA levels of ATF4, CHOP, GADD34 and DNAJA3 compared to non-treated cells.
GTPP pre-treatment reduced arsenite-induced SG assembly from 90% to 14%, 95% to 28% and 91% to 35% after 4, 6 or 8 h treatments, respectively.
GTPP pre-treatment reduced arsenite-induced eIF2α phosphorylation levels by 3 to 4-fold compared to arsenite-treated cells.
Paraquat pre-treatment reduced the average size of arsenite-induced SGs from 0.97 μm2 to 0.66 μm2 and increased the average number from 18 to 39 per cell.
GTPP treatment upregulated HSP90AA1 mRNA by 4 to 6-fold, and HSP90AB1 and DYRK3 by 2 to 3-fold at later time points.
Quotes
"UPRmt activation by GTPP or paraquat results in PERK-mediated activation of the ISR, accompanied with transient SG formation, in the case of GTTP."
"UPRmt-induced upregulation of the GADD34 protects cells against persistent SG assembly and preventing SG formation improved mitochondrial functions upon UPRmt induction."
"UPRmt activation by GTPP also inhibited the formation of eIF2α-independent SGs, and, the size and number of both eIF2α-dependent and independent SGs were altered in cells treated with paraquat compared to non-treated."