Abstract
Mitochondria form highly dynamic networks in which organelles constantly fuse and divide. The relevance of mitochondrial dynamics is evident from its implication in various human pathologies, including cancer or neurodegenerative, endocrine and cardiovascular diseases. Dynamin-related protein 1 (DRP1) is a key regulator of mitochondrial fission that oligomerizes at the mitochondrial outer membrane and hydrolyzes GTP to drive mitochondrial fragmentation. Previous studies demonstrated that DRP1 recruitment and mitochondrial fission is promoted by actin polymerization at the mitochondrial surface, controlled by the actin regulatory proteins inverted formin 2 (INF2) and Spire1C. These studies suggested the requirement of additional actin regulatory activities to control DRP1-mediated mitochondrial fission. Here we show that the actin-depolymerizing protein cofilin1, but not its close homolog actin-depolymerizing factor (ADF), is required to maintain mitochondrial morphology. Deletion of cofilin1 caused mitochondrial DRP1 accumulation and fragmentation, without altering mitochondrial function or other organelles’ morphology. Mitochondrial morphology in cofilin1-deficient cells was restored upon (i) re-expression of wild-type cofilin1 or a constitutively active mutant, but not of an actin-binding-deficient mutant, (ii) pharmacological destabilization of actin filaments and (iii) genetic depletion of DRP1. Our work unraveled a novel function for cofilin1-dependent actin dynamics in mitochondrial fission, and identified cofilin1 as a negative regulator of mitochondrial DRP1 activity. We conclude that cofilin1 is required for local actin dynamics at mitochondria, where it may balance INF2/Spire1C-induced actin polymerization.
Highlights
Mitochondria are crucially important for a number of cellular processes including energy metabolism, Ca2+-buffering or apoptosis.[1,2] The mitochondrial network is continuously shaped by fission and fusion events, and any disturbance in mitochondrial dynamics alters mitochondrial morphology and may affect mitochondrial function.[3]
In Cfl1− / −-mouse embryonic fibroblasts (MEFs), mitochondrial fragmentation was associated with elevated mitochondrial dynamin-related protein 1 (DRP1) levels, and mitochondrial morphology was restored (i) by a constitutive active cofilin[1] mutant, but not by an actin-binding-deficient cofilin[1] mutant, (ii) by acute destabilization of F-actin and (iii) by siRNA-mediated DRP1 knockdown
While we found fragmented mitochondria upon genetic inactivation of cofilin[1], mitochondrial morphology was unchanged in actindepolymerizing factor (ADF)-deficient MEFs
Summary
Mitochondria are crucially important for a number of cellular processes including energy metabolism, Ca2+-buffering or apoptosis.[1,2] The mitochondrial network is continuously shaped by fission and fusion events, and any disturbance in mitochondrial dynamics alters mitochondrial morphology and may affect mitochondrial function.[3]. Mitochondrial recruitment of DRP1 and its oligomerization at the outer membrane are key events in mitochondrial fission.[15] The mechanisms that act upstream of DRP1 recruitment and oligomerization are not fully understood, but several recent studies proposed a role for actin in these processes.[16,17,18] These studies evolved a model in which actin polymerization drives the initial constriction of the mitochondrial tube that is required for DRP1 oligomerization and mitochondrial fission.[16] they identified actin regulators relevant for mitochondrial fission, for example, inverted formin 2 (INF2) that is located in the membrane of the endoplasmic reticulum (ER) and works in conjunction with mitochondrial Spire1C.19,20 These studies suggested the requirement of additional actin regulatory activities to finetune actin dynamics at the mitochondrial surface, which may control DRP1-mediated mitochondrial fission.[16,20]. Mitochondrial fragmentation was associated with elevated mitochondrial DRP1 levels, and mitochondrial morphology was restored by (i) re-expression
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call