PMID- 19437551
OWN - NLM
STAT- MEDLINE
DCOM- 20100112
LR  - 20131121
IS  - 1097-4547 (Electronic)
IS  - 0360-4012 (Linking)
VI  - 87
IP  - 12
DP  - 2009 Sep
TI  - Mitochondrial dysfunction in a neural cell model of spinal muscular atrophy.
PG  - 2748-56
LID - 10.1002/jnr.22106 [doi]
AB  - Mutations of the survival motor neuron (SMN) gene in spinal muscular atrophy 
      (SMA) lead to anterior horn cell death. The cause is unknown, but motor neurons 
      depend substantially on mitochondrial oxidative phosphorylation (OxPhos) for 
      normal function. Therefore, mitochondrial parameters were analyzed in an SMA cell 
      culture model using small interfering RNA (siRNA) transfection that decreased Smn 
      expression in NSC-34 cells to disease levels. Smn siRNA knock-down resulted in 
      35% and 66% reduced Smn protein levels 48 and 72 hr posttransfection, 
      respectively. ATP levels were reduced by 14% and 26% at 48 and 72 hr 
      posttransfection, respectively, suggesting decreased ATP production or increased 
      energy demand in neural cells. Smn knock-down resulted in increased mitochondrial 
      membrane potential and increased free radical production. Changes in activity of 
      cytochrome c oxidase (CcO), a key OxPhos component, were observed at 72 hr with a 
      26% increase in oxygen consumption. This suggests a compensatory activation of 
      the aerobic pathway, resulting in increased mitochondrial membrane potentials, a 
      condition known to lead to the observed increase in free radical production. 
      Further testing suggested that changes in ATP at 24 hr precede observable indices 
      of cell injury at 48 hr. We propose that energy paucity and increased 
      mitochondrial free radical production lead to accumulated cell damage and 
      eventual cell death in Smn-depleted neural cells. Mitochondrial dysfunction may 
      therefore be important in SMA pathology and may represent a new therapeutic 
      target.
FAU - Acsadi, Gyula
AU  - Acsadi G
AD  - Children's Hospital of Michigan, Carman and Ann Adams Department of Pediatrics, 
      Detroit, Michigan, USA.
FAU - Lee, Icksoo
AU  - Lee I
FAU - Li, Xingli
AU  - Li X
FAU - Khaidakov, Magomed
AU  - Khaidakov M
FAU - Pecinova, Alena
AU  - Pecinova A
FAU - Parker, Graham C
AU  - Parker GC
FAU - Huttemann, Maik
AU  - Huttemann M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci Res
JT  - Journal of neuroscience research
JID - 7600111
RN  - 0 (Free Radicals)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Smn1 protein, mouse)
RN  - 0 (Survival of Motor Neuron 1 Protein)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 1.9.3.1 (Electron Transport Complex IV)
SB  - IM
MH  - Adenosine Triphosphate/metabolism
MH  - Animals
MH  - Cells, Cultured
MH  - Down-Regulation/genetics
MH  - Electron Transport Complex IV/metabolism
MH  - Energy Metabolism/physiology
MH  - Free Radicals/metabolism
MH  - Membrane Potential, Mitochondrial/physiology
MH  - Mice
MH  - Mitochondria/metabolism
MH  - Mitochondrial Diseases/*metabolism/physiopathology
MH  - Motor Neurons/*metabolism/pathology
MH  - Muscular Atrophy, Spinal/*metabolism/physiopathology
MH  - *Oxidative Phosphorylation
MH  - Oxidative Stress/physiology
MH  - RNA, Small Interfering/genetics
MH  - Spinal Cord/*metabolism/physiopathology
MH  - Survival of Motor Neuron 1 Protein/genetics/*metabolism
EDAT- 2009/05/14 09:00
MHDA- 2010/01/13 06:00
CRDT- 2009/05/14 09:00
PHST- 2009/05/14 09:00 [entrez]
PHST- 2009/05/14 09:00 [pubmed]
PHST- 2010/01/13 06:00 [medline]
AID - 10.1002/jnr.22106 [doi]
PST - ppublish
SO  - J Neurosci Res. 2009 Sep;87(12):2748-56. doi: 10.1002/jnr.22106.