Mitochondrial Dysfunction in Parkinson’s Disease—Cause or Consequence?

Abstract

James Parkinson first described the motor symptoms of the disease that took his name over 200 years ago. While our knowledge of many of the changes that occur in this condition has increased, it is still unknown what causes this neurodegeneration and why it only affects some individuals with advancing age. Here we review current literature to discuss whether the mitochondrial dysfunction we have detected in Parkinson’s disease is a pathogenic cause of neuronal loss or whether it is itself a consequence of dysfunction in other pathways. We examine research data from cases of idiopathic Parkinson’s with that from model systems and individuals with familial forms of the disease. Furthermore, we include data from healthy aged individuals to highlight that many of the changes described are also present with advancing age, though not normally in the presence of severe neurodegeneration. While a definitive answer to this question may still be just out of reach, it is clear that mitochondrial dysfunction sits prominently at the centre of the disease pathway that leads to catastrophic neuronal loss in those affected by this disease.

CNP mediated selective toxicity on melanoma cells is accompanied by mitochondrial dysfunction

“…Quality control of mitochondria is crucial for the cell, because the loss of mitochondrial function is associated with various diseases, e.g. heart failure [80] or Parkinson´s disease [81]. However, in our melanoma cell model a nanoceria triggered and H 2 O 2 mediated mitochondrial dysfunction is desired to force the tumor cells to undergo apoptosis.…”

In Vivo Mitochondrial Function in Idiopathic and Genetic Parkinson’s Disease

“…Several lines of research suggest that mitochondrial dysfunction plays a critical role in the development of both idiopathic and familial PD [4,5]. Indeed, various studies reported impairments in the respiratory chain due to environmental toxins (e.g., rotenone) that are powerful inhibitors of mitochondrial Complex I while post-mortem studies found widespread impairments in Complex I and Complex II of the respiratory chain in SNPC, hippocampus, putamen, and pedunculopontine nucleus of PD patients [4,6,7].…”

“…In the last year, genetic studies are suppling further evidence on the critical role played by mitochondria in the pathogenesis of PD [4,5]. Among the many pathogenic gene mutations, autosomal recessive Parkin and PINK1 mutations seem to be strictly linked to mitochondrial dysfunctions [10].…”

“…Furthermore, PINK1 mutations cause Ca 2+ overload in mitochondria and impairments in Complex I and Complex III of the respiratory chain [15,16]. As well, GBA gene mutation is another mutation linked to PD development [5]. Whereas homozygous GBA mutation cause Gaucher disease (GD), GBA heterozygosity is a potential risk factor for developing PD with an earlier age of onset and a major risk to develop dementia compared to idiopathic PD [17].…”

MGluR5 Modulation Effect on Protein Degradation in Parkinson's Disease

“…The motor dysfunctions that characterize PD are believed to stem from on the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and the corresponding loss of their downstream terminals in the striatum. Dopaminergic neurons appear to be particularly vulnerable to mitochondrial damage and autophagy dysfunction (Chen et al, 2019;Sato et al, 2018). While mitochondrial dysregulation is associated with oxidative stress and diminished energetic supply to the cell, the inhibition of autophagy observed affects the ability of the cell to manage misfolded proteins that are characteristic of PD pathology.…”