Mitochondria and Parkinson’s Disease: Clinical, Molecular, and Translational Aspects

Abstract

Mitochondrial dysfunction represents a well-established player in the pathogenesis of both monogenic and idiopathic Parkinson’s disease (PD). Initially originating from the observation that mitochondrial toxins cause PD, findings from genetic PD supported a contribution of mitochondrial dysfunction to the disease. Here, proteins encoded by the autosomal recessively inherited PD genes Parkin, PTEN-induced kinase 1 (PINK1), and DJ-1 are involved in mitochondrial pathways. Additional evidence for mitochondrial dysfunction stems from models of autosomal-dominant PD due to mutations in alpha-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2). Moreover, patients harboring alterations in mitochondrial polymerase gamma (POLG) often exhibit signs of parkinsonism. While some molecular studies suggest that mitochondrial dysfunction is a primary event in PD, others speculate that it is the result of impaired mitochondrial clearance. Most recent research even implicated damage-associated molecular patterns released from non-degraded mitochondria in neuroinflammatory processes in PD. Here, we summarize the manifold literature dealing with mitochondria in the context of PD. Moreover, in light of recent advances in the field of personalized medicine, patient stratification according to the degree of mitochondrial impairment followed by mitochondrial enhancement therapy may hold potential for at least a subset of genetic and idiopathic PD cases. Thus, in the second part of this review, we discuss therapeutic approaches targeting mitochondrial dysfunction with the aim to prevent or delay neurodegeneration in PD.

Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities

“…The most frequent mutation of LRRK2 (G2019S) causes an increase in its kinase activity, but it is unclear how this leads to PD. LRRK2 has been shown to be linked to mitochondrial dysfunction through regulation of mitochondrial motility; it has been shown to work in concert with PARKIN and PINK1 to modulate mitophagy [194,195]. Studies indicate that PGC-1α and the NAD-dependent protein deacetylase SIRT1 play a central role in cell metabolism and mitochondrial biogenesis [196,197]; deacetylation of PGC-1α by SIRT1 causes its activation and the transcription of genes involved in antioxidant defense [198][199][200].…”

A mechanistic review of Parkin activation

“…However, mutations at so-called "PARK" loci are estimated to underly the pathogenesis of <5% of all PD cases. Remarkably, the evidence on genetic predispositions and environmental factors both highlighted that the aetiology of PD involves proteins implicated in maintenance of mitochondrial function or degradation of dysfunctional mitochondria [7].…”

Protective Effects of Flavonoids Against Mitochondriopathies and Associated Pathologies: Focus on the Predictive Approach and Personalized Prevention

“…Recent progress in 3P medicine demonstrates that patient stratification and individualized patient profiling are instrumental for cost-effective targeted prevention and treatments tailored to the person [4,5,7,9]. Individualized evaluation of the mitochondrial impairments [190,191] is essential for the risk assessment related to mitochondriopathies and associated pathologies, including but not restricted to cancer, CVDs, and neurodegenerative disorders [192][193][194]. Targeting mitochondrial homeostasis is a promising innovation in the overall therapeutic strategy.…”