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Unravelling mitochondrial pathways to Parkinson's disease

Celardo, I; Martins, LM; Gandhi, S; (2014) Unravelling mitochondrial pathways to Parkinson's disease. British Journal of Pharmacology , 171 (8) pp. 1943-1957. 10.1111/bph.12433. Green open access

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Abstract

Mitochondria are essential for cellular function due to their role in ATP production, calcium homeostasis and apoptotic signalling. Neurons are heavily reliant on mitochondrial integrity for their complex signalling, plasticity and excitability properties, and to ensure cell survival over decades. The maintenance of a pool of healthy mitochondria that can meet the bioenergetic demands of a neuron, is therefore of critical importance; this is achieved by maintaining a careful balance between mitochondrial biogenesis, mitochondrial trafficking, mitochondrial dynamics and mitophagy. The molecular mechanisms that underlie these processes are gradually being elucidated. It is widely recognized that mitochondrial dysfunction occurs in many neurodegenerative diseases, including Parkinson's disease. Mitochondrial dysfunction in the form of reduced bioenergetic capacity, increased oxidative stress and reduced resistance to stress, is observed in several Parkinson's disease models. However, identification of the recessive genes implicated in Parkinson's disease has revealed a common pathway involving mitochondrial dynamics, transport, turnover and mitophagy. This body of work has led to the hypothesis that the homeostatic mechanisms that ensure a healthy mitochondrial pool are key to neuronal function and integrity. In this paradigm, impaired mitochondrial dynamics and clearance result in the accumulation of damaged and dysfunctional mitochondria, which may directly induce neuronal dysfunction and death. In this review, we consider the mechanisms by which mitochondrial dysfunction may lead to neurodegeneration. In particular, we focus on the mechanisms that underlie mitochondrial homeostasis, and discuss their importance in neuronal integrity and neurodegeneration in Parkinson's disease.

Type: Article
Title: Unravelling mitochondrial pathways to Parkinson's disease
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/bph.12433
Publisher version: http://dx.doi.org/ 10.1111/bph.12433
Language: English
Additional information: Copyright © 2013 The Authors. British Journal of Pharmacology published by John Wiley &. Sons Ltd on behalf of The British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License,(https://creativecommons.org/licenses/by-nc/3.0/) which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Keywords: Mitochondria, Parkinson's Disease, Mitophagy, Free Radicals, Respiratory Chain, Pink1, Parkin, Oxidative Stress, Calcium, Unfolded Protein Response, Endoplasmic-reticulum Stress, Ubiquitin-proteasome System, Substantia-nigra Neurons, Alpha-synuclein, Oxidative Stress, Axonal-transport, Cell-death, Complex-i, Damaged Mitochondria
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
URI: http://discovery.ucl.ac.uk/id/eprint/1528308
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