Migrasome-driven mitocytosis relieves mitochondrial damage induced by chikungunya virus TF and 6K

Chikungunya virus (CHIKV) infection induces the formation of migrasomes, yet their specific role in CHIKV pathogenesis remains unclear. This study explores the mechanisms underlying mitochondrial damage induced by CHIKV 181 clone 25 (CHIKV 181/25) and the role of migrasomes in mitigating this damage. Using cultured cell lines, we assessed the impact of CHIKV infection on mitochondrial integrity and function, with particular emphasis on the viroporin proteins transframe (TF) and 6K. We utilized fluorescence microscopy and transmission electron microscopy to visualize the interplay between migrasome formation and damaged mitochondria. Additionally, calcium imaging assays were conducted to evaluate intracellular calcium levels, and RNA sequencing was performed to examine gene expression. Our results demonstrated that CHIKV infection leads to mitochondrial damage, mediated by the action of TF and 6K. Notably, migrasomes induced by nonstructural protein 1 (nsP1) effectively clearing impaired mitochondria through mitocytosis. Furthermore, we identified the arginine residue R37 within the viroporin proteins of CHIKV as crucial for inducing mitochondrial damage through elevated intracellular calcium levels. Importantly, R37 within TF from other alphaviruses is also critical for mitochondrial damage. In conclusion, our findings elucidate the complex interplay between CHIKV and mitochondrial dysfunction, positioning migrasomes as potential mediators in alleviating CHIKV-induced mitochondrial damage.