PMID- 24659784
OWN - NLM
STAT- MEDLINE
DCOM- 20140627
LR  - 20211021
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 289
IP  - 19
DP  - 2014 May 9
TI  - Essential roles of neutral ceramidase and sphingosine in mitochondrial 
      dysfunction due to traumatic brain injury.
PG  - 13142-54
LID - 10.1074/jbc.M113.530311 [doi]
AB  - In addition to immediate brain damage, traumatic brain injury (TBI) initiates a 
      cascade of pathophysiological events producing secondary injury. The biochemical 
      and cellular mechanisms that comprise secondary injury are not entirely 
      understood. Herein, we report a substantial deregulation of cerebral sphingolipid 
      metabolism in a mouse model of TBI. Sphingolipid profile analysis demonstrated 
      increases in sphingomyelin species and sphingosine concurrently with 
      up-regulation of intermediates of de novo sphingolipid biosynthesis in the brain. 
      Investigation of intracellular sites of sphingosine accumulation revealed an 
      elevation of sphingosine in mitochondria due to the activation of neutral 
      ceramidase (NCDase) and the reduced activity of sphingosine kinase 2 (SphK2). The 
      lack of change in gene expression suggested that post-translational mechanisms 
      are responsible for the shift in the activities of both enzymes. 
      Immunoprecipitation studies revealed that SphK2 is complexed with NCDase and 
      cytochrome oxidase (COX) subunit 1 in mitochondria and that brain injury hindered 
      SphK2 association with the complex. Functional studies showed that sphingosine 
      accumulation resulted in a decreased activity of COX, a rate-limiting enzyme of 
      the mitochondrial electron transport chain. Knocking down NCDase reduced 
      sphingosine accumulation in mitochondria and preserved COX activity after the 
      brain injury. Also, NCDase knockdown improved brain function recovery and 
      lessened brain contusion volume after trauma. These studies highlight a novel 
      mechanism of secondary TBI involving a disturbance of sphingolipid-metabolizing 
      enzymes in mitochondria and suggest a critical role for mitochondrial sphingosine 
      in promoting brain injury after trauma.
FAU - Novgorodov, Sergei A
AU  - Novgorodov SA
AD  - From the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South 
      Carolina 29401.
FAU - Riley, Christopher L
AU  - Riley CL
FAU - Yu, Jin
AU  - Yu J
FAU - Borg, Keith T
AU  - Borg KT
FAU - Hannun, Yusuf A
AU  - Hannun YA
FAU - Proia, Richard L
AU  - Proia RL
FAU - Kindy, Mark S
AU  - Kindy MS
FAU - Gudz, Tatyana I
AU  - Gudz TI
LA  - eng
GR  - R01 CA172517/CA/NCI NIH HHS/United States
GR  - R37 GM043825/GM/NIGMS NIH HHS/United States
GR  - I01 BX001104/BX/BLRD VA/United States
GR  - I01 RX000331/RX/RRD VA/United States
GR  - P30 GM103339/GM/NIGMS NIH HHS/United States
GR  - I01 RX000206/RX/RRD VA/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20140321
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Nerve Tissue Proteins)
RN  - EC 1.9.3.1 (Electron Transport Complex IV)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.- (sphingosine kinase)
RN  - EC 3.5.1.23 (Alkaline Ceramidase)
RN  - NGZ37HRE42 (Sphingosine)
SB  - IM
MH  - Alkaline Ceramidase/genetics/*metabolism
MH  - Animals
MH  - Brain/*metabolism/pathology
MH  - Brain Injuries/genetics/*metabolism/pathology
MH  - Electron Transport Complex IV/genetics/metabolism
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Mitochondria/genetics/*metabolism
MH  - Nerve Tissue Proteins/genetics/*metabolism
MH  - Phosphotransferases (Alcohol Group Acceptor)/genetics/metabolism
MH  - Sphingosine/genetics/*metabolism
PMC - PMC4036326
OTO - NOTNLM
OT  - Brain
OT  - Cell Death
OT  - Mitochondria
OT  - Respiratory Chain
OT  - Sphingolipid
EDAT- 2014/03/25 06:00
MHDA- 2014/06/28 06:00
PMCR- 2015/05/09
CRDT- 2014/03/25 06:00
PHST- 2014/03/25 06:00 [entrez]
PHST- 2014/03/25 06:00 [pubmed]
PHST- 2014/06/28 06:00 [medline]
PHST- 2015/05/09 00:00 [pmc-release]
AID - S0021-9258(20)38798-6 [pii]
AID - M113.530311 [pii]
AID - 10.1074/jbc.M113.530311 [doi]
PST - ppublish
SO  - J Biol Chem. 2014 May 9;289(19):13142-54. doi: 10.1074/jbc.M113.530311. Epub 2014 
      Mar 21.