Is Disrupted Mitophagy a Central Player to Parkinson's Disease Pathology?

Abstract

Whilst the pathophysiology at a cellular level has been defined, the cause of Parkinson's disease (PD) remains poorly understood. This neurodegenerative disorder is associated with impaired dopamine transmission in the substantia nigra, and protein accumulations known as Lewy bodies are visible in affected neurons. Cell culture models of PD have indicated impaired mitochondrial function, so the focus of this paper is on the quality control processes involved in and around mitochondria. Mitochondrial autophagy (mitophagy) is the process through which defective mitochondria are removed from the cell by internalisation into autophagosomes which fuse with a lysosome. This process involves many proteins, notably including PINK1 and parkin, both of which are known to be coded on genes associated with PD. Normally in healthy individuals, PINK1 associates with the outer mitochondrial membrane, which then recruits parkin, activating it to attach ubiquitin proteins to the mitochondrial membrane. PINK1, parkin, and ubiquitin cooperate to form a positive feedback system which accelerates the deposition of ubiquitin on dysfunctional mitochondria, resulting in mitophagy. However, in hereditary PD, the genes encoding PINK1 and parkin are mutated, resulting in proteins that are less efficient at removing poorly performing mitochondria, leaving cells more vulnerable to oxidative stress and ubiquitinated inclusion bodies, such as Lewy bodies. Current research that looks into the connection between mitophagy and PD is promising, already yielding potentially therapeutic compounds; until now, pharmacological support for the mitophagy process has not been part of the therapeutic arsenal. Continued research in this area is warranted.

Keywords: lewy body; mitophagy; parkin; parkinson's disease; pink1.

Figure 1. Figure showing Parkinson’s disease patient from the front and from the side. His face is expressionless, his posture is stooped forward, and he has difficulty walking.

Figure taken from [5], and permission was obtained from the original publisher to reproduce the content.

Figure 2. Swallow-tails indicated by arrows (right) present in a healthy female (A) and healthy male (B), or lack thereof in Parkinson’s disease patients (left), female (A) and male (B).

Figure taken from [14], and permission was obtained from the original publisher to reproduce the content.

Figure 3. Lewy bodies (pink circular) present in brain tissue.

Figure taken from [19], and permission was obtained from the original publisher to reproduce the content.

Figure 4. Model of the life cycle of mitochondria.

Fusion events are rapidly followed by fission. Daughter mitochondria become solitary for a period before fusing again. Daughters with depolarised membranes may either recover their membrane potential, or are removed by mitophagy. Figure taken from [37], and permission was obtained from the original publisher to reproduce the content.

Figure 5. A comparison of healthy mitochondria (A) and damaged mitochondria (B) showing the processing of PINK1 by TOM, TIM, PARL, MPP, and the N-end rule pathway (A), or the accumulation of PINK1 on the OMM and recruitment of parkin (B).

Also indicated within the TOM complex is the minor subunit Tomm7, without which the functionality of the entire TOM ceases. PINK1: PTEN-induced kinase 1; Parkin: Parkinson juvenile disease protein 2; UBR1: ubiquitin protein ligase E3 component N-recognin 1; UBR2: ubiquitin protein ligase E3 component N-recognin 2; UBR4: ubiquitin protein ligase E3 component N-recognin 4; TOM: translocase of outer-membrane complex; TIM23: mitochondrial import inner membrane translocase subunit; OMM: outer mitochondrial membrane; IMS: intermembrane space; IMM: inner mitochondrial membrane; Tomm7: translocase of outer mitochondrial membrane 7; MPP: mitochondrial processing peptidase; PARL: presenilin-associated rhomboid-like protein Figure taken from [10], and permission was obtained from the original publisher to reproduce the content.

Figure 6. : Domain architecture of PINK1 (a), showing mitochondrial targeting sequence (MTS), the transmembrane domain (TMD), and the kinase domain.

Some cellular processes influenced by PINK1 are shown (b) indicating a wide range of areas of activity. MTS: mitochondrial targeting sequence; TMD: transmembrane domain; MPP: mitochondrial processing peptidase; PARL: presenilin-associated rhomboid-like protein; Ser228, Ser402: phosphorylation sites in PINK1; ROS: reactive oxygen species; Ub: ubiquitin; NAD: nicotinamide adenine dinucleotide; NADH: reduced form of NAD; NdufA10: NADH:ubiquinone oxidoreductase subunit A10; IMM: inner mitochondrial membrane; IMS: intermembrane space Figure taken from [52], and permission was obtained from the original publisher to reproduce the content.

Figure 7. Feedback loops as PINK1, ubiquitin and polyubiquitin enhance the migration of parkin.

Which then strengthens the action of PINK1 (A) and (B). Panel (C) shows a hypothetical graph indicating low phosphorylation of ubiquitin where reversal would be possible (blue line) and passing the threshold where damage becomes persistent and the mitochondrion is destroyed (red line). Figure taken from [69], and permission was obtained from the original publisher to reproduce the content.

Figure 8. Mitophagy processes in yeast (left), showing Atg32 stabilisation on defective mitochondria and its subsequent interaction with Atg11 and/or Atg8 to associate with an isolation membrane for lysosomal degradation.

Red blood cells (centre) dispose of mitochondria through a mechanism thought to involve the membrane protein NIX. PINK1-parkin-induced mitophagy (right). Atg32, Atg11, Atg8: autophagy proteins; WXXL: a conserved amino acid motif associated with LC3; NIX: NIP3-like protein X; LC3: microtubule-associated protein 1A/1B-light chain 3. Figure taken from [82], and permission was obtained from the original publisher to reproduce the content.

Figure 9. When mitochondria are healthy, PINK1 is degraded (a). When mitochondria are compromised, PINK1 and parkin recruit ubiquitin to label mitochondria for mitophagy (b).

PINK1: PTEN-induced kinase 1; PARL: presenilins-associated rhomboid-like protein; OMM: outer mitochondrial membrane; IMM: inner mitochondrial membrane; NDP52: calcium binding and coiled-coil domain 2; OPTN: optineurin; TBK1: TANK-binding kinase 1. Figure taken from [109], and permission was obtained from the original publisher to reproduce the content.

Figure 10. Ubiquinone, also known as coenzyme Q10.

Figure 11. Model of dysfunctional mitophagy leading to increased reactive oxygen species, formation of Lewy bodies, cell dysfunction and death of sensitive dopaminergic neurons—leading to PD.

PINK1: PTEN-induced kinase 1.

Figure 12. Structures of metformin (left) and nicotinamide (right)—both of which have been associated with the enhancement of mitophagy.