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.
authors: Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, Florida 33133, USA.
authors: Alicia M
authors: AM
authors: Pickrell
authors: Hirokazu
authors: H
authors: Fukui
authors: Xiao
authors: X
authors: Wang
authors: Milena
authors: M
authors: Pinto
authors: Carlos T
authors: CT
authors: Moraes
mesh_terms: D000367:Age Factors; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D053903:DNA Breaks, Double-Stranded; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D015252:Deoxyribonucleases, Type II Site-Specific / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D014450:Electron Transport Complex III / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D066298:In Vitro Techniques; D008279:Magnetic Resonance Imaging / Q000379:methods; D018782:Maze Learning / Q000502:physiology; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000150:complications / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D008954:Models, Biological; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010085:Oxidative Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D045442:Rotarod Performance Test; D013053:Spectrophotometry / Q000379:methods; D014404:Tubulin / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; D014404:Tubulin; D003576:Electron Transport Complex IV; C024388:CTGCAG-specific type II deoxyribonucleases; D015252:Deoxyribonucleases, Type II Site-Specific; D025261:Mitochondrial Proton-Translocating ATPases; D014450:Electron Transport Complex III