Resolution of collided ribosomes by ZNF598 is required for Adipocyte Energy Regulation

Le 22 octobre 2025 à 11h00 Séminaire

Adipose tissue is the central energy-storing organ that strongly influences whole-body metabolism. Beige and brown subtypes of adipocytes additionally dissipate energy in the form of heat. Thermal or dietary challenges can trigger various hormonal signals, including adrenergic stimulation, that drive the transition from white to beige adipocytes. In brown/beige adipocytes, higher mitochondrial activity compared to white adipocytes is correlated with an enhanced rate of protein synthesis. Therefore, we hypothesize that higher translation rates in beige/brown adipocytes make them more prone to translational stress. To resolve translational stress, cells have evolved different translational surveillance pathways. Activation of ribosome quality control (RQC), where ubiquitin-protein ligase zinc finger protein 598 (ZNF598) is a key activator, resolves collided ribosomes. Recent studies suggest that enhanced RQC promotes mitochondrial fitness. However, the impact of RQC on beige and brown adipocytes has not been defined so far.

We showed that the RQC and ZNF598 pathway is activated in brown and beige adipocytes by β-adrenergic stimulation, cold challenge, and dietary intervention. Further analyses revealed that ZNF598 is specifically required for mitochondrial respiration in beige and brown adipocytes. Moreover, in the absence of ZNF598, β-adrenergic stimulation failed to induce mitochondrial biogenesis in adipocytes. Importantly, overexpression of ZNF598 in adipocytes was sufficient to enhance mitochondrial biogenesis and function. Suggesting that RQC works with suboptimal efficiency in unstimulated conditions in brown/beige adipocytes. Indeed, transgenic overexpression of ZNF598 in the adipose tissue of mice enhanced energy dissipation by animals, elevated adipose tissue activity, and protected from diet-induced metabolic imbalance. Consistently, deletion of ZNF598 resulted in malfunction of adipose tissue, leading to systemic glucose intolerance. 

In conclusion, we found that RQC and ZNF598 are essential for mitochondrial function and biogenesis in beige/brown adipocytes. Enhancing the suboptimal efficiency of RQC in these cells boosts mitochondrial content and function, protecting against metabolic overload and diseases. These findings shift our understanding of mechanisms governing mitochondrial function in beige/brown adipocytes and open new possibilities for therapeutic interventions.