Unravelling mitochondrial pathways to Parkinson's disease

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.

Keywords: PARKIN; PINK1; Parkinson's disease; calcium; free radicals; mitochondria; mitophagy; oxidative stress; respiratory chain.

Figure 1

Modulation of mitochondrial dysfunction by the PINK1/PARKIN pathway. (A) Mitochondrial dynamics contribute to the maintenance of mitochondrial integrity. Upon mitochondrial dysfunction, mtDNA mutations or misfolded proteins accumulate. The PINK1/PARKIN axis inhibits the fusion process to avoid the spreading of damaged mitochondrial components. However, this axis also enhances the fission process to induce the physical separation of damaged mitochondria. Healthy components are rescued and damaged ones are eliminated by mitophagy. (B) Mitophagy is required to eliminate damaged mitochondria. When the organelle is deeply impaired, PINK1 recruits PARKIN for ubiquitination of outer membrane proteins, which labels irreversibly damaged mitochondria for mitophagy. (C) Mitochondrial trafficking is arrested upon mitochondrial dysfunction. PINK1 inhibits mitochondrial movement along microtubules, recruits PARKIN for ubiquitination and induces ubiquitin-dependent degradation of Miro. The above information is summarized from references discussed in the text.

Figure 2

Cellular processes acting downstream of mitochondrial dysfunction. Increasing levels of mitochondrial damage lead to correspondingly higher levels of mitochondrial dysfunction (here represented by the categorical classifiers ‘low’, ‘medium’ and ‘high’). Low levels of mitochondrial dysfunction are counteracted at the molecular level by the PINK1 pathway. This acts on intra-organellar proteases and chaperones, such as HtrA2/OMI and TRAP1, and suppresses the Miro-dependent transport of dysfunctional mitochondria. The combined output of these processes is the restoration of mitochondrial health. Higher levels of mitochondrial dysfunction might overwhelm the molecular QC. In this case, PINK1 promotes the degradation of mitochondria with ‘medium’ levels of dysfunction through mitophagy. This is the organellar QC pathway. Finally, if both molecular and organellar QC pathways downstream of PINK1 fail, the mitochondria will ultimately release pro-apoptotic proteins and mtDNA, resulting in either apoptosis or inflammation. The above information is summarized from references discussed in the text.