PMID- 30190335
OWN - NLM
STAT- MEDLINE
DCOM- 20190528
LR  - 20230201
IS  - 1757-4684 (Electronic)
IS  - 1757-4676 (Print)
IS  - 1757-4676 (Linking)
VI  - 10
IP  - 10
DP  - 2018 Oct
TI  - Mutations in TIMM50 compromise cell survival in OxPhos-dependent metabolic 
      conditions.
LID - 10.15252/emmm.201708698 [doi]
LID - e8698
AB  - 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.
CI  - (c) 2018 The Authors. Published under the terms of the CC BY 4.0 license.
FAU - Reyes, Aurelio
AU  - Reyes A
AUID- ORCID: 0000-0003-2876-2202
AD  - MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK 
      art@mrc-mbu.cam.ac.uk mdz21@mrc-mbu.cam.ac.uk.
FAU - Melchionda, Laura
AU  - Melchionda L
AD  - Unit of Molecular Neurogenetics, Foundation Carlo Besta Neurological 
      Institute-IRCCS, Milan, Italy.
FAU - Burlina, Alberto
AU  - Burlina A
AD  - Division of Inherited Metabolic Diseases, Department of Pediatrics, University 
      Hospital Padova, Padova, Italy.
FAU - Robinson, Alan J
AU  - Robinson AJ
AD  - MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
FAU - Ghezzi, Daniele
AU  - Ghezzi D
AUID- ORCID: 0000-0002-9358-1566
AD  - Unit of Molecular Neurogenetics, Foundation Carlo Besta Neurological 
      Institute-IRCCS, Milan, Italy.
FAU - Zeviani, Massimo
AU  - Zeviani M
AUID- ORCID: 0000-0002-9067-5508
AD  - MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK 
      art@mrc-mbu.cam.ac.uk mdz21@mrc-mbu.cam.ac.uk.
LA  - eng
GR  - MC_U105674181/MRC_/Medical Research Council/United Kingdom
GR  - 322424/ERC_/European Research Council/International
GR  - MC_UU_00015/8/MRC_/Medical Research Council/United Kingdom
GR  - MC_UP_1002/1/MRC_/Medical Research Council/United Kingdom
GR  - MC_UU_00015/5/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - EMBO Mol Med
JT  - EMBO molecular medicine
JID - 101487380
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (Mitochondrial Precursor Protein Import Complex Proteins)
RN  - 0 (TIMM50 protein, human)
SB  - IM
MH  - Brain Diseases/diagnosis/pathology/*physiopathology
MH  - Cell Survival
MH  - Cells, Cultured
MH  - Female
MH  - Fibroblasts/pathology
MH  - Genetic Complementation Test
MH  - Humans
MH  - Infant
MH  - Italy
MH  - Membrane Transport Proteins/*genetics
MH  - Mitochondrial Diseases/diagnosis/pathology/*physiopathology
MH  - Mitochondrial Precursor Protein Import Complex Proteins
MH  - *Mutation
MH  - *Oxidative Phosphorylation
PMC - PMC6180300
OTO - NOTNLM
OT  - OxPhos
OT  - TIMM50
OT  - bioenergetic dysfunction
OT  - mitochondrial import
EDAT- 2018/09/08 06:00
MHDA- 2019/05/29 06:00
PMCR- 2018/10/01
CRDT- 2018/09/08 06:00
PHST- 2018/09/08 06:00 [pubmed]
PHST- 2019/05/29 06:00 [medline]
PHST- 2018/09/08 06:00 [entrez]
PHST- 2018/10/01 00:00 [pmc-release]
AID - emmm.201708698 [pii]
AID - EMMM201708698 [pii]
AID - 10.15252/emmm.201708698 [doi]
PST - ppublish
SO  - EMBO Mol Med. 2018 Oct;10(10):e8698. doi: 10.15252/emmm.201708698.