GTPBP8 is required for mitoribosomal biogenesis and mitochondrial translation

Abstract

Mitochondrial translation occurs on the mitochondrial ribosome, also known as the mitoribosome. The assembly of mitoribosomes is a highly coordinated process. During mitoribosome biogenesis, various assembly factors transiently associate with the nascent ribosome, facilitating the accurate and efficient construction of the mitoribosome. However, the specific factors involved in the assembly process, the precise mechanisms, and the cellular compartments involved in this vital process are not yet fully understood. In this study, we discovered a crucial role for GTP-binding protein 8 (GTPBP8) in the assembly of the mitoribosomal large subunit (mt-LSU) and mitochondrial translation. GTPBP8 is identified as a novel GTPase located in the matrix and peripherally bound to the inner mitochondrial membrane. Importantly, GTPBP8 is specifically associated with the mt-LSU during its assembly. Depletion of GTPBP8 leads to an abnormal accumulation of mt-LSU, indicating that GTPBP8 is critical for proper mt-LSU assembly. Furthermore, the absence of GTPBP8 results in reduced levels of fully assembled 55S monosomes. This impaired assembly leads to compromised mitochondrial translation and, consequently, impaired mitochondrial function. The identification of GTPBP8 as an important player in these processes provides new insights into the molecular mechanisms underlying mitochondrial protein synthesis and its regulation.

GTPBP8 modulates mitochondrial fission through a Drp1-dependent process

“…In this present study, we report on the role of GTPBP8 in modulating mitochondrial fission. Apart from the impaired assembly of mt-LSU and the consequent compromised mitochondrial translation previously seen ( Wang et al, 2023 ), we here also observed a pronounced alteration in mitochondrial morphology following GTPBP8 depletion, characterized by a strikingly elongated and interconnected appearance. Further exploration into the proteins involved in mitochondrial dynamics illuminated an intriguing observation: an elevation in the levels of Drp1 phosphorylated at S637 (Drp1 S637-PO 4 ).…”

“…S1A ). We recently reported that GTPBP8 resides in the matrix side of the mitochondrial inner membrane and is peripherally associated with the inner membrane ( Wang et al, 2023 ). To investigate the functions of GTPBP8 within mitochondria, we conducted a comprehensive exploration of its impact through loss-of-function experiments in mammalian cells, utilizing siRNA-mediated protein knockdown.…”

“…GTPBP8 is a mitoribosomal assembly factor, and its knockdown causes mitoribosomal assembly and protein translation defects, leading to impaired mitochondrial function, including reduced respiratory capacity ( Wang et al, 2023 ). To explore whether the loss of other mitoribosomal assembly factors elicits a similar effect on mitochondrial morphology, we examined changes in mitochondrial morphology following the depletion of three other mitoribosomal assembly factors, GTPBP5, GTPBP7 and GTPBP10 ( Kotani et al, 2013 ; Lavdovskaia et al, 2018 ; Maiti et al, 2020 ) ( Fig.…”

“…We recently reported that GTPBP8 localizes to the mitochondrial inner membrane and functions in the assembly of the mitoribosomal large subunit (mt-LSU) ( Wang et al, 2023 ). In this present study, we report on the role of GTPBP8 in modulating mitochondrial fission.…”

“…This intricate regulation of mitochondrial dynamics significantly contributes to overall cellular health and function. The physiological relevance of mitochondrial dynamics came to light with the discovery that alterations in these processes are associated with various human pathologies, including cancer and neurodegeneration ( Chan, 2006 ; Kraus and Ryan, 2017 ; Quiles and Gustafsson, 2022 ; Wang et al, 2023 ).…”