The article begins by introducing SGs as cytoplasmic ribonucleoprotein granules formed through phase separation in response to stress. It discusses SGs’ roles in RNA metabolism, translation regulation, and their implication in diseases, particularly neurodegenerative disorders. A major focus is on SGs' dynamic interactions with other cellular components—including processing bodies (PBs), neuronal granules, nuclear organelles (like PML nuclear bodies and paraspeckles), and membrane-bound organelles (such as lysosomes, ER, mitochondria, and the Golgi complex). It also evaluates experimental methods (e.g., biochemical fractionation, proximity labeling) used to dissect SG composition and interaction networks.
Key points of the review include:

1. Stress granules' role in neurodegeneration: SGs are linked to neurodegenerative diseases such as ALS, FTD, and Alzheimer’s. Mutations in SG-associated proteins (e.g., TDP-43, FUS, Tau) can cause pathological aggregates. Disrupted SG dynamics due to these mutations may impair neuronal function, emphasizing SGs as both biomarkers and therapeutic targets in neurodegeneration.
2. Interactions between SGs and other organelles: SGs interact physically and functionally with both membraneless and membrane-bound organelles, including PBs, paraspeckles, lysosomes, ER, and mitochondria. These interactions help coordinate stress responses but can be disrupted in disease, contributing to cellular dysfunction. For example, Annexin A11 links SGs with lysosomes, affecting RNA granule transport, especially in neurons.
3. Techniques for SG analysis: The paper highlights methods like biochemical fractionation, proximity labeling (e.g., APEX, BioID), and mass spectrometry for identifying SG components and interactions. Each method has specific advantages and limitations regarding labeling precision, range, and temporal resolution. Integrating multiple techniques allows for comprehensive profiling of SG-related networks and their dynamics under stress.
4. SGs share components with other organelles: SGs overlap significantly in composition with other organelles, especially those involved in RNA metabolism. GO and KEGG analyses show shared components function in splicing and mRNA regulation, processes also implicated in ALS pathogenesis. These shared proteins are essential in understanding organelle crosstalk and the role of SGs in disease.

The review underscores that SGs serve as critical hubs for coordinating cellular stress responses through interactions with various organelles. Their dysregulation is closely associated with multiple diseases, especially neurodegenerative disorders. Understanding SG formation, dynamics, and inter-organelle communication provides vital insights into cellular homeostasis and pathology. Advances in experimental methods, particularly those enabling high-resolution tracking of SG components and their interactions, will be instrumental in uncovering new therapeutic targets. Future research should focus on dissecting the precise molecular mechanisms underlying SG-organelle interactions and their alterations in disease to develop targeted interventions. The work entitled “ Stress granules and organelles: coordinating cellular responses in health and disease” was published on Protein & Cell (published on Oct. 23, 2024).
DOI：https://doi.org/10.1093/procel/pwae057