Mitochondrial Stress Triggers Dynamic Stress Granule Formation and Disassembly to Maintain Organelle Homeostasis

Kernekoncepter

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.

Resumé

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.

Statistik

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.

Citater

"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."

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Activation of the mitochondrial unfolded protein response regulates the dynamic formation of stress granules

by Lopez-Nieto ... kl. www.biorxiv.org 10-26-2023

https://www.biorxiv.org/content/10.1101/2023.10.26.564187v1

Dybere Forespørgsler

How do the specific compositions of UPRmt-induced SGs differ from other stress-induced SGs, and how do these compositional differences impact mitochondrial homeostasis?

The specific compositions of UPRmt-induced stress granules (SGs) differ from other stress-induced SGs in terms of the proteins and RNA components that are sequestered within them. UPRmt-induced SGs are formed in response to mitochondrial stress and are characterized by the presence of specific mitochondrial proteins and RNA molecules that are involved in maintaining mitochondrial homeostasis. These SGs contain components that are essential for mitochondrial function and quality control, such as chaperones, proteases, and mitochondrial ribosomal proteins. The presence of these specific components in UPRmt-induced SGs reflects their role in coordinating the cellular response to mitochondrial stress and ensuring the proper functioning of the mitochondria.
The compositional differences between UPRmt-induced SGs and other stress-induced SGs impact mitochondrial homeostasis by providing a specialized platform for the regulation of key processes related to mitochondrial function. The unique composition of UPRmt-induced SGs allows them to sequester and concentrate specific proteins and RNA molecules that are crucial for maintaining mitochondrial health. By organizing these components within the SGs, cells can efficiently coordinate the response to mitochondrial stress, facilitate the repair of damaged mitochondrial proteins, and promote the restoration of mitochondrial function. Therefore, the specific compositions of UPRmt-induced SGs play a critical role in preserving mitochondrial homeostasis under stressful conditions.

How do the potential mechanisms by which the persistence of SGs during mitochondrial stress impairs mitochondrial respiration and function?

The persistence of stress granules (SGs) during mitochondrial stress can impair mitochondrial respiration and function through several potential mechanisms:

Sequestration of key mitochondrial proteins: SGs can sequester essential mitochondrial proteins, such as metabolic enzymes or components of the electron transport chain, leading to their inactivation or reduced availability for mitochondrial functions. This sequestration can disrupt normal mitochondrial processes and impair mitochondrial respiration.

Disruption of mitochondrial dynamics: Persistent SGs can physically interact with mitochondria, altering their dynamics and morphology. This interaction can interfere with mitochondrial fusion and fission processes, affecting mitochondrial function and respiration.

Impact on cellular energy metabolism: SGs can alter the availability of metabolic enzymes and substrates required for mitochondrial respiration. The sequestration of key metabolic enzymes within SGs can disrupt cellular energy metabolism, leading to a decrease in ATP production and impaired mitochondrial respiration.

Induction of oxidative stress: Prolonged presence of SGs can lead to the accumulation of reactive oxygen species (ROS) within cells. Increased oxidative stress can damage mitochondrial components, such as mitochondrial DNA and proteins, impairing mitochondrial function and respiration.

Overall, the persistence of SGs during mitochondrial stress can disrupt normal mitochondrial processes, interfere with cellular energy metabolism, and induce oxidative stress, collectively impairing mitochondrial respiration and function.

Could the dynamic regulation of SG assembly and disassembly be exploited as a therapeutic strategy to maintain mitochondrial health in diseases associated with mitochondrial dysfunction?

The dynamic regulation of stress granule (SG) assembly and disassembly could be potentially exploited as a therapeutic strategy to maintain mitochondrial health in diseases associated with mitochondrial dysfunction. Here are some ways in which this dynamic regulation could be leveraged for therapeutic purposes:

Targeting SG disassembly pathways: Modulating the pathways involved in SG disassembly, such as chaperones or kinases that promote SG dissolution, could be a therapeutic approach to prevent the persistence of SGs and their detrimental effects on mitochondrial function. Enhancing the clearance of SGs could help restore normal mitochondrial processes and improve mitochondrial health in disease conditions.

Regulating SG formation: By targeting the factors that control SG assembly, such as stress sensors or signaling molecules involved in SG formation, it may be possible to prevent the excessive formation of SGs during mitochondrial stress. Modulating the dynamics of SG assembly could help maintain mitochondrial homeostasis and prevent mitochondrial dysfunction in disease states.

Developing SG-targeted therapies: Designing therapies that specifically target SG components or disrupt SG formation could be a novel approach to mitigate the impact of SGs on mitochondrial function. By selectively modulating SG dynamics, it may be possible to restore normal mitochondrial respiration and function in diseases associated with mitochondrial dysfunction.

In conclusion, the dynamic regulation of SG assembly and disassembly represents a promising therapeutic target for maintaining mitochondrial health in conditions characterized by mitochondrial dysfunction. By manipulating the processes involved in SG dynamics, it may be possible to restore normal mitochondrial function and improve outcomes in diseases associated with mitochondrial impairment.