Credit:The extracellular matrix integrates mitochondrial homeostasis
Recently, a paradigm-shifting research published in Cell, explored the intricate relationship between the extracellular matrix (ECM) and mitochondrial homeostasis, revealing a previously unrecognized communication pathway that played a crucial role in cellular stress responses and immune defense.
The ECM: A Sentinel of the Extracellular Environment
The ECM is a complex network of proteins and carbohydrates that surrounds cells and provides structural support, as well as a microenvironment that influences cellular behavior. It is not only a barrier to intercellular communication but also a reservoir for signaling molecules, including growth factors and cytokines. The ECM is particularly vulnerable to damage by pathogens, which secrete enzymes like hyaluronidases to disrupt its integrity.
Hyaluronan: A Key ECM Component and Its Role in Mitochondrial Homeostasis
Hyaluronan (HA), a major component of the ECM, is a linear polymer of repeating disaccharide units. It exists in two forms: high molecular weight (HMW) and low molecular weight (LMW). HMW HA promotes anti-inflammatory and antiproliferative effects, while LMW HA fragments are pro-inflammatory and trigger cell migration and proliferation.
The study focused on TMEM2, a cell surface hyaluronidase that specifically degrades HMW HA into LMW fragments. By manipulating TMEM2 expression in human fibroblasts and the nematode C. elegans, the researchers investigated the impact of ECM remodeling on mitochondrial function.
ECM Remodeling Alters Mitochondrial Function
The researchers found that overexpression of TMEM2 (TMEM2-OE) led to increased degradation of HA in the ECM, resulting in a series of cellular changes. Cells with OE TMEM2 exhibited increased sensitivity to mitochondrial stressors like rotenone and nutrient deprivation, indicating compromised mitochondrial function. This was associated with increased mitochondrial fragmentation, reduced mitochondrial respiration, and increased mitochondrial reactive oxygen species (ROS) production. Similarly, knockout of TMEM2 (TMEM2-KO) resulted in resistance to mitochondrial stress and fewer mitochondrial puncta, suggesting increased mitochondrial fusion and reduced mitochondrial fragmentation.
TGF-β Signaling Mediates ECM-Mitochondria Communication
To uncover the molecular mechanism behind these observations, the researchers performed a CRISPR-KO screen to identify genes that played a role in the ECM-mitochondria communication pathway. Surprisingly, they found that knocking out either of the TGF-β receptor subunits (TGFBR1 or TGFBR2) or using a chemical inhibitor of TGFBR1 (SB431542) rescued the mitochondrial stress sensitivity of TMEM2-OE cells.
Further investigation revealed that TGF-β ligands, such as TGF-β1 and TGF-β2, were stored in the ECM in an inactive form and were activated upon ECM remodeling. The TGF-β ligands then bound to the TGFBR1/TGFBR2 receptor complex, triggering downstream SMAD signaling. This signaling pathway was highly conserved across species and played a central role in regulating ECM remodeling and immune responses.
TGF-β-SMAD Signaling Induces Mitochondrial Fission
The researchers next explored the effects of TGF-β signaling on mitochondrial morphology and function. They found that TGF-β1 treatment promoted the accumulation of enlarged mitochondrial puncta, indicative of increased mitochondrial fragmentation, and reduced mitochondrial respiration. This effect was reversed by SB431542, suggesting that TGF-β signaling directly inhibited mitochondrial respiration. TGF-β1 also increased mitochondrial ROS levels, consistent with the increased ROS production observed in TMEM2-OE cells.
RNA-seq analysis revealed that TGF-β1 treatment upregulated genes associated with mitochondrial fission, such as DNM1, DRP1, UCP2, MTFP1, and RALA. This suggested that TGF-β-SMAD signaling might directly promote the expression of mitochondrial fission genes to regulate mitochondrial homeostasis.
ECM Remodeling Enhances Immune Responses
The researchers hypothesized that the ECM-mitochondria communication pathway might play a role in immune defense. They found that TMEM2-OE cells exhibit increased expression of anti-viral response genes, including type I interferon-associated immune genes. This was abrogated by knocking out TGFBR1, indicating that TGF-β signaling is required for this effect.
In C. elegans, OE of hTMEM2 (hTMEM2-OE) conferred robust resistance to two pathogenic bacteria, S. marcescens and E. faecalis. hTMEM2-OE animals also exhibited increased tolerance to E. faecalis infection, suggesting enhanced immune responses. This protection was dependent on the TGF-β signaling pathway and the mitochondrial stress response genes atfs-1 and skn-1.
The ECM-Mitochondria Crosstalk: A Primitive Immune Pathway
The findings suggested that the ECM-mitochondria communication pathway represented an ancient immune mechanism that detects ECM damage caused by pathogens or mechanical stress. This damage triggered the release of TGF-β ligands, which activated TGF-β-SMAD signaling. The downstream effects included mitochondrial fission, reduced mitochondrial respiration, and increased ROS production, ultimately leading to enhanced immune signaling and protection against infections.
Implications and Future Directions
This research provides a novel understanding of how the ECM and mitochondria communicate to regulate cellular stress responses and immune defense. The ECM-mitochondria crosstalk may play a crucial role in protecting cells from pathogens and promoting tissue repair.
Further investigation is needed to explore the following aspects:
Mechanisms of ECM remodeling: Understanding how different ECM components are remodeled in specific physiological and pathological contexts will provide insights into the regulation of the ECM-mitochondria crosstalk.
Diversity of ECM-derived alarmins: Identifying other ECM components that can activate TGF-β signaling and other signaling pathways will reveal the complexity of ECM-mitochondria communication.
Cell-type-specific signaling mechanisms: Investigating whether other cell types, particularly innate immune cells, have similar signaling mechanisms will provide a more comprehensive understanding of the ECM-mitochondria crosstalk in immune defense.
Metabolic rewiring: Exploring the effects of ECM remodeling on cellular metabolism may reveal additional mechanisms by which the ECM-mitochondria crosstalk regulates immune responses.
Applications in longevity and immunity: Manipulating HA integrity in different tissues could potentially extend mammalian life spans and enhance immune activation efficiency.
This research opens new avenues for understanding the complex interplay between the ECM and mitochondria and has implications for various areas of biology, including immunology, aging, and tissue repair.
Reference:
Zhang H, Tsui CK, Garcia G, Joe LK, Wu H, Maruichi A, Fan W, Pandovski S, Yoon PH, Webster BM, Durieux J, Frankino PA, Higuchi-Sanabria R, Dillin A. The extracellular matrix integrates mitochondrial homeostasis. Cell. 2024 Jun 24:S0092-8674(24)00638-X.
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