Mutations in TIMM50 compromise cell survival in OxPhos-dependent metabolic conditions.
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Authors
Melchionda, Laura
Burlina, Alberto
Robinson, Alan J
Publication Date
2018-10Journal Title
EMBO Mol Med
ISSN
1757-4676
Publisher
EMBO
Volume
10
Issue
10
Language
eng
Type
Article
Physical Medium
Print
Metadata
Show full item recordCitation
Reyes, A., Melchionda, L., Burlina, A., Robinson, A. J., Ghezzi, D., & Zeviani, M. (2018). Mutations in TIMM50 compromise cell survival in OxPhos-dependent metabolic conditions.. EMBO Mol Med, 10 (10) https://doi.org/10.15252/emmm.201708698
Abstract
TIMM50 is an essential component of the TIM23 complex, the mitochondrial inner membrane machinery that imports cytosolic proteins containing a mitochondrial targeting presequence into the mitochondrial inner compartment. Whole exome sequencing (WES) identified compound heterozygous pathogenic mutations in TIMM50 in an infant patient with rapidly progressive, severe encephalopathy. Patient fibroblasts presented low levels of TIMM50 and other components of the TIM23 complex, lower mitochondrial membrane potential, and impaired TIM23-dependent protein import. As a consequence, steady-state levels of several components of mitochondrial respiratory chain were decreased, resulting in decreased respiration and increased ROS production. Growth of patient fibroblasts in galactose shifted energy production metabolism toward oxidative phosphorylation (OxPhos), producing an apparent improvement in most of the above features but also increased apoptosis. Complementation of patient fibroblasts with TIMM50 improved or restored these features to control levels. Moreover, RNASEH1 and ISCU mutant fibroblasts only shared a few of these features with TIMM50 mutant fibroblasts. Our results indicate that mutations in TIMM50 cause multiple mitochondrial bioenergetic dysfunction and that functional TIMM50 is essential for cell survival in OxPhos-dependent conditions.
Keywords
OxPhos, TIMM50, bioenergetic dysfunction, mitochondrial import, Brain Diseases, Cell Survival, Cells, Cultured, Female, Fibroblasts, Genetic Complementation Test, Humans, Infant, Italy, Membrane Transport Proteins, Mitochondrial Diseases, Mitochondrial Precursor Protein Import Complex Proteins, Mutation, Oxidative Phosphorylation
Sponsorship
Medical Research Council (MC_UP_1002/1)
European Research Council (322424)
Medical Research Council (MC_UU_00015/8)
MRC (MC_UU_00015/8)
Medical Research Council (MC_U105674181)
Identifiers
External DOI: https://doi.org/10.15252/emmm.201708698
This record's URL: https://www.repository.cam.ac.uk/handle/1810/285390
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