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Cell metabolism affects selective vulnerability in PINK1-associated Parkinson's disease

Yao, Z; Gandhi, S; Burchell, VS; Plun-Favreau, H; Wood, NW; Abramov, AY; (2011) Cell metabolism affects selective vulnerability in PINK1-associated Parkinson's disease. Journal of Cell Science , 124 (24) pp. 4194-4202. 10.1242/jcs.088260. Green open access

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Abstract

Mitochondrial dysfunction plays a primary role in the pathogenesis of Parkinson's disease (PD), particularly in autosomal recessive forms of the disease caused by mutations encoding PINK1. Although mitochondrial pathology can be demonstrated in many cell types, it is neurons that bear the brunt of cell death in PD. We studied the mitochondrial physiology of neurons and muscle cells with loss of function of the nuclear encoded mitochondrial protein PINK1. PINK1 is widely expressed in many types of tissues, but deficiency selectively induces death in neurons. We report here that the same genetic defect results in opposing phenotypes in different cell types, depending on the metabolic properties of the cell. Thus, PINK1-deficient myocytes exhibit high basal mitochondrial membrane potential (Δψm), whereas PINK1-deficient neurons have been shown to exhibit a low Δψm. PINK1 deficiency induces impaired respiration in both cell types, with a concomitant increase in glycolytic activity. We demonstrate that the high glycolytic capacity in myocytes compared with neurons enables them to produce more ATP and, therefore, compensates for the metabolic defects induced by PINK1 deficiency. Furthermore, the high Δψm generated in PINK1 knockout (KO) muscle mitochondria enables them to buffer cytosolic Ca2+ fluxes, rendering them resistant to Ca2+ stress effectively. Conversely, PINK1 KO neurons were previously shown to develop mitochondrial Ca2+ overload and Ca2+-induced mitochondrial depolarisation. Prevention of Ca2+ dysregulation in myocytes might therefore account for the sparing of these cells in PD.

Type: Article
Title: Cell metabolism affects selective vulnerability in PINK1-associated Parkinson's disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.1242/jcs.088260
Publisher version: https://doi.org/10.1242/jcs.088260
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: ATP, PINK1, Mitochondria, Myocyte, Neuron
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: http://discovery.ucl.ac.uk/id/eprint/1337201
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