The striatum is highly susceptible to mitochondrial oxidative phosphorylation dysfunctions

Alicia M. Pickrell, Hirokazu Fukui, Xiao Wang, Milena Pinto, Carlos T Moraes

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Neuronal oxidative phosphorylation (OXPHOS) deficiency has been associated with a variety of neurodegenerative diseases, including Parkinson's disease and Huntington's disease. However, it is not clear how mitochondrial dysfunction alone can lead to a preferential elimination of certain neuronal populations in vivo. We compared different types of neuronal populations undergoing the same OXPHOS deficiency to determine their relative susceptibility and mechanisms responsible for selective neuron vulnerability. We used a mouse model expressing a mitochondria-targeted restriction enzyme, PstI or mito-PstI. The expression of mito-PstI induces double-strand breaks in the mitochondrial DNA(mtDNA), leading to OXPHOS deficiency, mostly due to mtDNA depletion. We targeted mito-PstI expression to the cortex, hippocampus, and striatum under the CaMKII-α promoter. Animals undergoing long-term expression of mito-PstI displayed a selective worsening of the striatum over cortical and hippocampal areas. Mito-PstI expression and mtDNA depletion were not worse in the striatum, but the latter showed the most severe defects in mitochondrial membrane potential, response to calcium, and survival. These results showed that the striatum is particularly sensitive to defects in OXPHOS possibly due to an increased reliance on OXPHOS function in this area and differences in response to physiological stimuli. These results may help explain the neuropathological features associated with Huntington's disease, which have been associated with OXPHOS defects.

Original languageEnglish
Pages (from-to)9895-9904
Number of pages10
JournalJournal of Neuroscience
Volume31
Issue number27
DOIs
StatePublished - Jul 6 2011

Fingerprint

Mitochondrial Diseases
Oxidative Phosphorylation
Mitochondrial DNA
Huntington Disease
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Mitochondrial Membrane Potential
Neurodegenerative Diseases
Population
Parkinson Disease
Hippocampus
Mitochondria
Calcium
Neurons

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

The striatum is highly susceptible to mitochondrial oxidative phosphorylation dysfunctions. / Pickrell, Alicia M.; Fukui, Hirokazu; Wang, Xiao; Pinto, Milena; Moraes, Carlos T.

In: Journal of Neuroscience, Vol. 31, No. 27, 06.07.2011, p. 9895-9904.

Research output: Contribution to journalArticle

Pickrell, Alicia M. ; Fukui, Hirokazu ; Wang, Xiao ; Pinto, Milena ; Moraes, Carlos T. / The striatum is highly susceptible to mitochondrial oxidative phosphorylation dysfunctions. In: Journal of Neuroscience. 2011 ; Vol. 31, No. 27. pp. 9895-9904.
@article{cbe2390bf7a94ef9aeb3d685f883f410,
title = "The striatum is highly susceptible to mitochondrial oxidative phosphorylation dysfunctions",
abstract = "Neuronal oxidative phosphorylation (OXPHOS) deficiency has been associated with a variety of neurodegenerative diseases, including Parkinson's disease and Huntington's disease. However, it is not clear how mitochondrial dysfunction alone can lead to a preferential elimination of certain neuronal populations in vivo. We compared different types of neuronal populations undergoing the same OXPHOS deficiency to determine their relative susceptibility and mechanisms responsible for selective neuron vulnerability. We used a mouse model expressing a mitochondria-targeted restriction enzyme, PstI or mito-PstI. The expression of mito-PstI induces double-strand breaks in the mitochondrial DNA(mtDNA), leading to OXPHOS deficiency, mostly due to mtDNA depletion. We targeted mito-PstI expression to the cortex, hippocampus, and striatum under the CaMKII-α promoter. Animals undergoing long-term expression of mito-PstI displayed a selective worsening of the striatum over cortical and hippocampal areas. Mito-PstI expression and mtDNA depletion were not worse in the striatum, but the latter showed the most severe defects in mitochondrial membrane potential, response to calcium, and survival. These results showed that the striatum is particularly sensitive to defects in OXPHOS possibly due to an increased reliance on OXPHOS function in this area and differences in response to physiological stimuli. These results may help explain the neuropathological features associated with Huntington's disease, which have been associated with OXPHOS defects.",
author = "Pickrell, {Alicia M.} and Hirokazu Fukui and Xiao Wang and Milena Pinto and Moraes, {Carlos T}",
year = "2011",
month = "7",
day = "6",
doi = "10.1523/JNEUROSCI.6223-10.2011",
language = "English",
volume = "31",
pages = "9895--9904",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "27",

}

TY - JOUR

T1 - The striatum is highly susceptible to mitochondrial oxidative phosphorylation dysfunctions

AU - Pickrell, Alicia M.

AU - Fukui, Hirokazu

AU - Wang, Xiao

AU - Pinto, Milena

AU - Moraes, Carlos T

PY - 2011/7/6

Y1 - 2011/7/6

N2 - Neuronal oxidative phosphorylation (OXPHOS) deficiency has been associated with a variety of neurodegenerative diseases, including Parkinson's disease and Huntington's disease. However, it is not clear how mitochondrial dysfunction alone can lead to a preferential elimination of certain neuronal populations in vivo. We compared different types of neuronal populations undergoing the same OXPHOS deficiency to determine their relative susceptibility and mechanisms responsible for selective neuron vulnerability. We used a mouse model expressing a mitochondria-targeted restriction enzyme, PstI or mito-PstI. The expression of mito-PstI induces double-strand breaks in the mitochondrial DNA(mtDNA), leading to OXPHOS deficiency, mostly due to mtDNA depletion. We targeted mito-PstI expression to the cortex, hippocampus, and striatum under the CaMKII-α promoter. Animals undergoing long-term expression of mito-PstI displayed a selective worsening of the striatum over cortical and hippocampal areas. Mito-PstI expression and mtDNA depletion were not worse in the striatum, but the latter showed the most severe defects in mitochondrial membrane potential, response to calcium, and survival. These results showed that the striatum is particularly sensitive to defects in OXPHOS possibly due to an increased reliance on OXPHOS function in this area and differences in response to physiological stimuli. These results may help explain the neuropathological features associated with Huntington's disease, which have been associated with OXPHOS defects.

AB - Neuronal oxidative phosphorylation (OXPHOS) deficiency has been associated with a variety of neurodegenerative diseases, including Parkinson's disease and Huntington's disease. However, it is not clear how mitochondrial dysfunction alone can lead to a preferential elimination of certain neuronal populations in vivo. We compared different types of neuronal populations undergoing the same OXPHOS deficiency to determine their relative susceptibility and mechanisms responsible for selective neuron vulnerability. We used a mouse model expressing a mitochondria-targeted restriction enzyme, PstI or mito-PstI. The expression of mito-PstI induces double-strand breaks in the mitochondrial DNA(mtDNA), leading to OXPHOS deficiency, mostly due to mtDNA depletion. We targeted mito-PstI expression to the cortex, hippocampus, and striatum under the CaMKII-α promoter. Animals undergoing long-term expression of mito-PstI displayed a selective worsening of the striatum over cortical and hippocampal areas. Mito-PstI expression and mtDNA depletion were not worse in the striatum, but the latter showed the most severe defects in mitochondrial membrane potential, response to calcium, and survival. These results showed that the striatum is particularly sensitive to defects in OXPHOS possibly due to an increased reliance on OXPHOS function in this area and differences in response to physiological stimuli. These results may help explain the neuropathological features associated with Huntington's disease, which have been associated with OXPHOS defects.

UR - http://www.scopus.com/inward/record.url?scp=79960079717&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79960079717&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.6223-10.2011

DO - 10.1523/JNEUROSCI.6223-10.2011

M3 - Article

C2 - 21734281

AN - SCOPUS:79960079717

VL - 31

SP - 9895

EP - 9904

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 27

ER -