Abstract
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease due to mutations in SACS, which encodes sacsin, a protein localized on the mitochondrial surface and possibly involved in mitochondrial dynamics. In view of the possible mitochondrial involvement of sacsin, we investigated mitochondrial activity at functional and molecular level in skin fibroblasts obtained from ARSACS patients. We observed remarkable bioenergetic damage in ARSACS cells, as indicated by reduced basal, adenosine triphosphate (ATP)-linked and maximal mitochondrial respiration rate, and by reduced respiratory chain activities and mitochondrial ATP synthesis. These phenomena were associated with increased reactive oxygen species production and oxidative nuclear DNA damage. Our results suggest that loss of sacsin is associated with oxidative stress and mitochondrial dysfunction, and thus highlight a novel mechanism in the pathogenesis of ARSACS. The involvement of mitochondria and oxidative stress in disease pathogenesis has been described in a number of other neurodegenerative diseases. Therefore, on the basis of our findings, which suggest a potential therapeutic role for antioxidant agents, ARSACS seems to fall within a larger group of disorders.
| Original language | English |
|---|---|
| Pages (from-to) | 2755-2763 |
| Number of pages | 9 |
| Journal | Journal of Neurology |
| Volume | 262 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Dec 1 2015 |
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Keywords
- ARSACS
- Mitochondrial dynamics
- Mitochondrial metabolism
- SACS
- Sacsin
ASJC Scopus subject areas
- Clinical Neurology
- Neurology
Cite this
Powerhouse failure and oxidative damage in autosomal recessive spastic ataxia of Charlevoix-Saguenay. / Criscuolo, Chiara; Procaccini, C.; Meschini, M. C.; Cianflone, A.; Carbone, R.; Doccini, S.; Devos, D.; Nesti, C.; Vuillaume, I.; Pellegrino, M.; Filla, A.; De Michele, G.; Matarese, G.; Santorelli, F. M.
In: Journal of Neurology, Vol. 262, No. 12, 01.12.2015, p. 2755-2763.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Powerhouse failure and oxidative damage in autosomal recessive spastic ataxia of Charlevoix-Saguenay
AU - Criscuolo, Chiara
AU - Procaccini, C.
AU - Meschini, M. C.
AU - Cianflone, A.
AU - Carbone, R.
AU - Doccini, S.
AU - Devos, D.
AU - Nesti, C.
AU - Vuillaume, I.
AU - Pellegrino, M.
AU - Filla, A.
AU - De Michele, G.
AU - Matarese, G.
AU - Santorelli, F. M.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease due to mutations in SACS, which encodes sacsin, a protein localized on the mitochondrial surface and possibly involved in mitochondrial dynamics. In view of the possible mitochondrial involvement of sacsin, we investigated mitochondrial activity at functional and molecular level in skin fibroblasts obtained from ARSACS patients. We observed remarkable bioenergetic damage in ARSACS cells, as indicated by reduced basal, adenosine triphosphate (ATP)-linked and maximal mitochondrial respiration rate, and by reduced respiratory chain activities and mitochondrial ATP synthesis. These phenomena were associated with increased reactive oxygen species production and oxidative nuclear DNA damage. Our results suggest that loss of sacsin is associated with oxidative stress and mitochondrial dysfunction, and thus highlight a novel mechanism in the pathogenesis of ARSACS. The involvement of mitochondria and oxidative stress in disease pathogenesis has been described in a number of other neurodegenerative diseases. Therefore, on the basis of our findings, which suggest a potential therapeutic role for antioxidant agents, ARSACS seems to fall within a larger group of disorders.
AB - Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease due to mutations in SACS, which encodes sacsin, a protein localized on the mitochondrial surface and possibly involved in mitochondrial dynamics. In view of the possible mitochondrial involvement of sacsin, we investigated mitochondrial activity at functional and molecular level in skin fibroblasts obtained from ARSACS patients. We observed remarkable bioenergetic damage in ARSACS cells, as indicated by reduced basal, adenosine triphosphate (ATP)-linked and maximal mitochondrial respiration rate, and by reduced respiratory chain activities and mitochondrial ATP synthesis. These phenomena were associated with increased reactive oxygen species production and oxidative nuclear DNA damage. Our results suggest that loss of sacsin is associated with oxidative stress and mitochondrial dysfunction, and thus highlight a novel mechanism in the pathogenesis of ARSACS. The involvement of mitochondria and oxidative stress in disease pathogenesis has been described in a number of other neurodegenerative diseases. Therefore, on the basis of our findings, which suggest a potential therapeutic role for antioxidant agents, ARSACS seems to fall within a larger group of disorders.
KW - ARSACS
KW - Mitochondrial dynamics
KW - Mitochondrial metabolism
KW - SACS
KW - Sacsin
UR - http://www.scopus.com/inward/record.url?scp=84947868504&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84947868504&partnerID=8YFLogxK
U2 - 10.1007/s00415-015-7911-4
DO - 10.1007/s00415-015-7911-4
M3 - Article
C2 - 26530509
AN - SCOPUS:84947868504
VL - 262
SP - 2755
EP - 2763
JO - Journal of Neurology
JF - Journal of Neurology
SN - 0340-5354
IS - 12
ER -