A study on the role of FKBP8 in mitochondrial fission and degradation

Abstract

Mitochondria change its shape continuously through fission and fusion which help to maintain functional mitochondria under metabolic or environmental stress condition. Dysfunction of such mitochondrial fusion and fission dynamics and degradation of mitochondria evokes failure of mitochondrial quality control and has been linked to several human diseases. Thus, identification of novel factor involved in mitochondrial dynamics and mitophagy are important and will provide mechanistic insight into mitochondria quality control. Here, I report that FKBP8, a FK506-binding protein 8 which is a member of the immunophilin protein family, has a critical role in mitochondrial fission and degradation. Ectopic expression of FKBP8 increased the numbers of cells showing mitochondrial fragmentation and induced drastic co-localization of GFP-LC3B as well as GFP-GABARAPL1 or GABARAPL2 with the mitochondria Deletion-mapping and mutagenesis analysis revealed that the N-terminal region was required for FKBP8-mediated LC3 recruitment onto mitochondria. Especially, the LIR#1 (24FEVL27) motif of FKBP8 was critical for the binding to LC3. Interestingly, ectopic expression of FKBP8 induced mitochondrial fragmentation and this ability was unique to FKBP8 among FKBP family. Conversely, knockdown of FKBP8 expression by RNA interference increased the volume and number of mitochondria. Especially, enlarged mitochondria was typically observed under electron microscope. FKBP8-induced mitochondrial fragmentation occurred independently of Drp1, BNIP3 and NIX, well known mitochondrial fission/mitophagic factors, but was abolished by mutation in the LIR#2 (93WLDI96). Further, I found that FKBP8 interacted with FIS1, a mitochondrial fission factor. But deletion in the LIR#2 (93WLDI96) or deletion in TPR domain of FKBP8 reduced the binding of FKBP8 to FIS1. In addition, knockdown of FKBP8 expression attenuated mitochondrial degradation under hypoxia. Together, these results suggest that FKBP8 mediates mitochondrial dynamics and degradation by binding to FIS1 through the LIR#2/TPR domain and perform mitophagic event by binding to LC3 through the LIR#1 motif.