Cofilin(s) and Mitochondria: Function Beyond Actin Dynamics

ADF/cofilins form a family of small, widely expressed actin-binding proteins, regulating actin dynamics in various cellular and physiological processes in all eukaryotes, from yeasts to animals. Changes in the expression of the ADF/cofilin family proteins have been demonstrated under various pathological conditions. The well-established role of cofilin in migration, invasion, epithelial-mesenchymal transition, apoptosis, resistance to radiotherapy and chemotherapy, immune escape, and transcriptional dysregulation in malignant tumors is primarily attributed to its actin-modifying activity. Moreover, drugs targeting this function of cofilin have been developed for cancer treatment. However, its multilevel regulation, highly diverse effects across various pathological conditions, and conflicting data on the functional consequences of altered cofilin expression have prompted us to explore additional roles of cofilin-beyond actin modulation-particularly its involvement in lipid metabolism and mitochondrial homeostasis. Here, we review recent data on the expression of ADF/cofilin family proteins in various pathologies, account for the mutations and post-translational modifications of these proteins and their functional consequences, dwell on the role of K63-type ubiquitination of cofilin for its involvement in lipid metabolism and mitochondrial homeostasis, more specifically, a process of mitochondrial division or mitofission, point out conflicting data in cofilin research, and describe prospects for future studies of cofilin functions.