Mitochondrial dysfunction in Parkinson's disease - a key disease hallmark with therapeutic potential

Abstract

Mitochondrial dysfunction is strongly implicated in the etiology of idiopathic and genetic Parkinson's disease (PD). However, strategies aimed at ameliorating mitochondrial dysfunction, including antioxidants, antidiabetic drugs, and iron chelators, have failed in disease-modification clinical trials. In this review, we summarize the cellular determinants of mitochondrial dysfunction, including impairment of electron transport chain complex 1, increased oxidative stress, disturbed mitochondrial quality control mechanisms, and cellular bioenergetic deficiency. In addition, we outline mitochondrial pathways to neurodegeneration in the current context of PD pathogenesis, and review past and current treatment strategies in an attempt to better understand why translational efforts thus far have been unsuccessful.

Keywords: Antioxidants; Electron transport chain; MPTP; Mitochondria; Mitochondrial dysfunction; Neuroprotective therapies; Parkinson’s disease; Synuclein.

Fig. 1

Mechanism of action of neurotoxins inducing PD. MPTP readily crosses the blood-brain barrier and is taken up by nearby astroglia which subsequently convert it to MPP⁺ via MAO-B. Extracellularly released MPP⁺ is then actively taken up via DAT and accumulates within mitochondria of DA neurons where it inhibits mitochondrial CI of the ETC resulting in ROS production and energetic deficiency. Similarly, the pesticide rotenone (Rot), due to its high lipophilicity, readily crosses biological membranes and reaches the inner mitochondrial membrane where it inhibits CI. In contrast, paraquat (PQ²⁺) relies on the LAT1 to cross the blood-brain barrier. Hereafter, it is taken up by DAT or OCT3 into DA neurons and generates ROS by redox cycling at CI and CIII of the ETC. Abbreviations: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); 1-methyl-4-phenylpyridinium (MPP⁺); coenzyme Q (CoQ); dopamine (DA); dopamine transporter (DAT); L-amino acid transporter (LAT1); mitochondrial Complex I (CI); mitochondrial Complex II (CII); mitochondrial Complex III (CIII); mitochondrial Complex IV (CIV); mitochondrial Complex V (CV); monoamino oxidase B (MAO-B); organic cation transporter 3 (OCT3); paraquat (PQ²⁺); reactive oxygen species (ROS); rotenone (Rot); vesicular monoamino transporter (VMAT). Created with BioRender.com

Fig. 2

Synucleinopathy-driven mechanisms of cellular dysfunction and death in PD. Abbreviations: mitochondrial permeability transition pore (mPTP); reactive oxygen species (ROS). Created with BioRender.com