GTPBP8 modulates mitochondrial fission through a Drp1-dependent process.

Publisher: Company of Biologists Country of Publication: England NLM ID: 0052457 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1477-9137 (Electronic) Linking ISSN: 00219533 NLM ISO Abbreviation: J Cell Sci Subsets: MEDLINE

Publication: Cambridge : Company of Biologists
Original Publication: London.

Dynamins*/metabolism ; Dynamins*/genetics ; Microtubule-Associated Proteins*/metabolism ; Microtubule-Associated Proteins*/genetics ; Mitochondria*/metabolism ; Mitochondrial Dynamics*/genetics ; Monomeric GTP-Binding Proteins*/genetics ; Monomeric GTP-Binding Proteins*/metabolism; Humans ; GTP Phosphohydrolases/metabolism ; GTP Phosphohydrolases/genetics ; GTP-Binding Proteins/metabolism ; GTP-Binding Proteins/genetics ; Mitochondrial Proteins/metabolism ; Mitochondrial Proteins/genetics ; Oxidative Stress ; Phosphorylation

Mitochondrial fission is a tightly regulated process involving multiple proteins and cell signaling. Despite extensive studies on mitochondrial fission factors, our understanding of the regulatory mechanisms remains limited. This study shows the critical role of a mitochondrial GTPase, GTPBP8, in orchestrating mitochondrial fission in mammalian cells. Depletion of GTPBP8 resulted in drastic elongation and interconnectedness of mitochondria. Conversely, overexpression of GTPBP8 shifted mitochondrial morphology from tubular to fragmented. Notably, the induced mitochondrial fragmentation from GTPBP8 overexpression was inhibited in cells either depleted of the mitochondrial fission protein Drp1 (also known as DNM1L) or carrying mutated forms of Drp1. Importantly, downregulation of GTPBP8 caused an increase in oxidative stress, modulating cell signaling involved in the increased phosphorylation of Drp1 at Ser637. This phosphorylation hindered the recruitment of Drp1 to mitochondria, leading to mitochondrial fission defects. By contrast, GTPBP8 overexpression triggered enhanced recruitment and assembly of Drp1 at mitochondria. In summary, our study illuminates the cellular function of GTPBP8 as a pivotal modulator of the mitochondrial division apparatus, inherently reliant on its influence on Drp1.
Competing Interests: Competing interests The authors declare no competing or financial interests.
(© 2024. Published by The Company of Biologists Ltd.)

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323670 Research Council of Finland; 1.3.5 Project for Disciplines of Excellence; Sichuan Province Science and Technology Support Program; Guangxi expert funding; Jane and Aatos Erkko Foundation; Special Fund for Distinguished Experts in Guangxi of China; 32000719 National Natural Science Foundation of China; ZYGD23011 Sichuan University; 2021M702362 China Postdoctoral Science Foundation; 23NSFSC2884 Science and Technology Department of Sichuan Province

Keywords: Drp1; Fission; GTPBP8; Mitochondria; Phosphorylation

EC 3.6.5.5 (DNM1L protein, human)
EC 3.6.5.5 (Dynamins)
EC 3.6.1.- (GTP Phosphohydrolases)
EC 3.6.1.- (GTP-Binding Proteins)
0 (Microtubule-Associated Proteins)
0 (Mitochondrial Proteins)
EC 3.6.5.2 (Monomeric GTP-Binding Proteins)

Date Created: 20240408 Date Completed: 20240430 Latest Revision: 20240830

20240830

PMC11112121

10.1242/jcs.261612

38587461