A mitocentric view of Parkinson's disease

Abstract

Parkinson's disease (PD) is a common neurodegenerative disease, yet the underlying causative molecular mechanisms are ill defined. Numerous observations based on drug studies and mutations in genes that cause PD point to a complex set of rather subtle mitochondrial defects that may be causative. Indeed, intensive investigation of these genes in model organisms has revealed roles in the electron transport chain, mitochondrial protein homeostasis, mitophagy, and the fusion and fission of mitochondria. Here, we attempt to synthesize results from experimental studies in diverse systems to define the precise function of these PD genes, as well as their interplay with other genes that affect mitochondrial function. We propose that subtle mitochondrial defects in combination with other insults trigger the onset and progression of disease, in both familial and idiopathic PD.

Keywords: PD genes; electron transport chain; mitochondria; mitochondrial dynamics; mitochondrial unfolded protein response; reactive oxygen species.

Figure 1

Proteins implicated in Parkinson’s disease (PD) maintain a healthy pool of mitochondria. The effects of PD-linked proteins (thick green line) on mitochondrial function can be divided into three different groups. Bioenergetics (yellow): Pink1 and Parkin regulate the turnover of several subunits of ETC complexes by the ubiquitin proteasome system (UPS). In addition, Pink1 supports complex I activity through a kinase cascade involving tricornered (trc) and mTORC2. Mitochondrially localized α-synuclein (α-syn), however, inhibits complex I. Oxidation of the mitochondrial phospholipid cardiolipin translocates this lipid from the inner to the outer mitochondrial membrane where it serves as a receptor for α-synuclein. Hence, in the presence of elevated levels of reactive oxygen species (ROS), mitochondrial α-synuclein import is increased. LRRK2 and DJ-1 regulate the activity of uncoupling proteins (UCPs), which preserve the mitochondrial membrane potential (MMP). Both PD proteins therefore indirectly maintain ATP production. Mitochondrial unfolded protein response (UPR^mt, blue): When activated, Pink1 phosphorylates the chaperone Trap1, a protein that protects mitochondrial proteins from ROS. In addition, Trap1 works with Hsp60 to refold imported proteins, sustaining mitochondrial protein homeostasis. In the presence of ROS, DJ-1 is translocated into mitochondria, where it interacts with the chaperone Mortalin to salvage oxidized proteins. Mitochondrial dynamics (orange): LRRK2 directs mitochondrial fission as it interacts with and recruits the mitochondrial fission protein Drp1. DJ-1 increases mitochondrial fission by regulating Drp1 levels, although the exact mechanism through which the chaperone executes this function is not clear. The E3 ubiquitin ligase Parkin inhibits mitochondrial fusion through ubiquitin-mediated degradation of the fusion protein Mitofusin (Mfn). Mitochondrial transport is regulated by the Pink1/Parkin pathway. Here, Parkin-mediated degradation of the adaptor protein Miro is thought to detach a dysfunctional mitochondrion from kinesin motor proteins, halting its transport. Finally, when a dysfunctional mitochondrion cannot be repaired, it is cleared through mitophagy. Under basal conditions, the protein kinase Pink1 is imported into the mitochondrial intermembrane space, where it is cleaved by 2 proteases and subsequently degraded. However, upon mitigation of the MMP, Pink1 is no longer cleaved. The protein then phosphorylates and activates the E3 ubiquitin ligase Parkin. Parkin, along with E2 ligases such as Rad6, initiates mitophagy by ubiquitinating target proteins.

Figure 2

The multiple hit model of Parkinson’s disease (PD). Top panel: In familial parkinsonism, for example due to loss of function of Parkin, several key aspects of mitochondrial homeostasis are mildly affected, including energy production, protein folding (UPRmt), or dynamics (fission and fusion). These defects interact and amplify one another, but a second hit, such as elevated endogenous reactive oxygen species (ROS) or cellular activity, is likely required to trigger neuronal dysfunction and loss in certain vulnerable cell types, such as in DA neurons. Bottom panel: In idiopathic PD, multiple hits, including both common and rare genomic variations at diverse susceptibility loci, may in combination cause similar, subtle, and distributed defects in mitochondrial function. α-Synuclein pathology, ROS, potential environmental factors, and the widespread cellular effects of aging further degrade mitochondrial activity. In a potential feedback mechanism, mitochondrial dysfunction may also promote α-synuclein aggregation, which in turn may further amplify mitochondrial defects, ultimately leading to neuronal dysfunction and cell death.