Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences

Abstract

Neurons are critically dependent on mitochondrial integrity based on specific morphological, biochemical, and physiological features. They are characterized by high rates of metabolic activity and need to respond promptly to activity-dependent fluctuations in bioenergetic demand. The dimensions and polarity of neurons require efficient transport of mitochondria to hot spots of energy consumption, such as presynaptic and postsynaptic sites. Moreover, the postmitotic state of neurons in combination with their exposure to intrinsic and extrinsic neuronal stress factors call for a high fidelity of mitochondrial quality control systems. Consequently, it is not surprising that mitochondrial alterations can promote neuronal dysfunction and degeneration. In particular, mitochondrial dysfunction has long been implicated in the etiopathogenesis of Parkinson's disease (PD), based on the observation that mitochondrial toxins can cause parkinsonism in humans and animal models. Substantial progress towards understanding the role of mitochondria in the disease process has been made by the identification and characterization of genes causing familial variants of PD. Studies on the function and dysfunction of these genes revealed that various aspects of mitochondrial biology appear to be affected in PD, comprising mitochondrial biogenesis, bioenergetics, dynamics, transport, and quality control.

Figure 1

Aetiology of Parkinson’s disease (PD) and possible links to mitochondrial integrity. Familial PD is caused by mutations in genes identified by linkage analyses that are inherited in an autosomal recessive or dominant manner. Sporadic PD is considered to be a complex neurodegenerative disease entity with both genetic susceptibility and environmental factors contributing to the etiopathogenesis. Recent genome-wide association studies have identified susceptibility loci, which in two cases (α-synuclein and LRRK2) overlap with classical PD genes, linking the aetiology of familial parkinsonism with that of sporadic PD. Both genetic and environmental factors influence various mitochondrial aspects, such as bioenergetics, dynamics, transport, and quality control.

Figure 2

Mechanism of PINK1- and parkin-induced mitophagy. (A) When the mitochondrial membrane potential is high, PINK1 is imported into mitochondria, proteolytically processed and rapidly degraded, resulting in mitochondria with low levels of endogenous PINK1 under basal conditions. (B) Under conditions of low membrane potential, for example, after uncoupling with CCCP, full-length PINK1 accumulates on the mitochondrial surface, which is essential for the translocation of parkin to mitochondria. Parkin then ubiquitinates mitochondrial proteins at the outer membrane, followed by the recruitment of adaptor proteins, such as p62, which link ubiquitinated cargo to the autophagic machinery. Damaged mitochondria are engulfed by phagophores, which mature into autophagosomes and fuse with lysosomes to autolysosomes, which eventually degrade their content.

Figure 3

Mitochondrial functions of PINK1 and parkin. (A) A linear pathway with PINK1 acting upstream of parkin is implicated in mediating degradation of damaged mitochondria via mitophagy. (B) PINK1 and parkin also affect mitochondrial functions via parallel pathways, possibly by acting on mitochondria independently from each other.

Figure 4

Physiological and pathophysiological functions of α-synuclein on membrane dynamics. Effects of α-synuclein on membrane fusion events can explain why both an increase of α-synuclein expression and a loss of α-synuclein have adverse effects. Overexpression of α-synuclein causes ER/Golgi vesicle trafficking defects and mitochondrial fragmentation, whereas α-synuclein deficiency affects SNARE complex assembly.

Figure 5

PD genes are implicated in various aspects of mitochondrial biology. Products of autosomal recessive PD genes (shown in green) or autosomal dominant PD genes (shown in red) directly or indirectly affect a wide spectrum of mitochondrial processes, including their life cycle, bioenergetic capacity, quality control, dynamic changes of morphology and connectivity (fusion, fission), subcellular distribution (transport), and the regulation of cell death pathways.