The genetic architecture of mitochondrial dysfunction in Parkinson's disease

Abstract

Mitochondrial impairment is a well-established pathological pathway implicated in Parkinson's disease (PD). Defects of the complex I of the mitochondrial respiratory chain have been found in post-mortem brains from sporadic PD patients. Furthermore, several disease-related genes are linked to mitochondrial pathways, such as PRKN, PINK1, DJ-1 and HTRA2 and are associated with mitochondrial impairment. This phenotype can be caused by the dysfunction of mitochondrial quality control machinery at different levels: molecular, organellar or cellular. Mitochondrial unfolded protein response represents the molecular level and implicates various chaperones and proteases. If the molecular level of quality control is not sufficient, the organellar level is required and involves mitophagy and mitochondrial-derived vesicles to sequester whole dysfunctional organelle or parts of it. Only when the impairment is too severe, does it lead to cell death via apoptosis, which defines the cellular level of quality control. Here, we review how currently known PD-linked genetic variants interfere with different levels of mitochondrial quality control. We discuss the graded risk concept of the most recently identified PARK loci (PARK 17-23) and some susceptibility variants in GBA, LRRK2 and SNCA. Finally, the emerging concept of rare genetic variants in candidates genes for PD, such as HSPA9, TRAP1 and RHOT1, complete the picture of the complex genetic architecture of PD that will direct future precision medicine approaches.

Keywords: Genetics; Mitochondria; Parkinson’s disease; Quality control; Risk factors.

Fig. 1

Graded risk concept for genes related to mitochondrial dysfunction in Parkinson disease. Severity of mitochondrial dysfunction is represented in a gradient from red (strong mitochondrial dysfunction) to yellow (moderate mitochondrial dysfunction). Figure adapted from Manolio et al.

Fig. 2

Organellar quality control. (a) Major mitochondrial dysfunction leads to a global MMP reduction (red). Miro1 ensures the arrest of mitochondrial transport along the microtubules (MT) by sensing the calcium concentration. PINK1 accumulates on the mitochondria and recruits Parkin. Parkin ubiquitinates various mitochondrial proteins that leads to the engulfment of mitochondria by the autophagosome. The autophagosome fuse with the lysosome and mitochondrial proteins become degraded by lysosomal enzymes. This process is called mitophagy. b Global mitochondrial dysfunction can be avoided by fission, induced by Drp1. The impaired daughter mitochondria (red) will then undergo mitophagy as well. c Mitochondria can also have a localised MMP reduction due to local increase of oxidised proteins (OxProt) or ROS. This leads to a budding of mitochondria-derived vesicles (MDVs) implicating a local activation of PINK1/Parkin pathway and recruitment of VPS35. MDVs then fuse with the lysosome. Healthy mitochondria (physiological MMP) are represented in blue, dysfunctional mitochondria (decreased MMP) are represented in red. Proteins in bold are linked to PD

Fig. 3

Molecular and cellular quality control. a In healthy mitochondria (blue), unfolded proteins from the cytoplasm enter by TOM and TIM. Inside the mitochondria, Mortalin and mtHsp60 help in the folding of proteins. b In case of increased level of misfolded proteins and ROS within the mitochondria (orange), the mtUPR pathway is activated. This leads to the increase of mitochondrial chaperones expression, Mortalin and mtHsp60, which help in the refolding of misfolded and oxidised proteins. TRAP1 and Omi/HtrA2 also help to refold or degrade the misfolded proteins. c In case of major cellular dysfunction, impaired mitochondria (red) triggers apoptosis. CHCHD2 allows relocalisation of Bax, which conjointly with Bak induces release of cytochrome c. TRAP1, mtHsp60 and mortalin can stimulate cytochrome c release and Omi/HtrA2 facilitates apoptosis by binding to IAPs. Also, alpha-synuclein increases Ca2+ transfer to the mitochondria that, when overloaded, induces apoptosis. Proteins in bold are linked to PD