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 journalArticlepeer-review

70 Scopus citations

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

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'The striatum is highly susceptible to mitochondrial oxidative phosphorylation dysfunctions'. Together they form a unique fingerprint.

Cite this