Targeting Mitochondrial Impairment in Parkinson's Disease: Challenges and Opportunities

Abstract

The underlying pathophysiology of Parkinson's disease is complex, but mitochondrial dysfunction has an established and prominent role. This is supported by an already large and rapidly growing body of evidence showing that the role of mitochondrial (dys)function is central and multifaceted. However, there are clear gaps in knowledge, including the dilemma of explaining why inherited mitochondriopathies do not usually present with parkinsonian symptoms. Many aspects of mitochondrial function are potential therapeutic targets, including reactive oxygen species production, mitophagy, mitochondrial biogenesis, mitochondrial dynamics and trafficking, mitochondrial metal ion homeostasis, sirtuins, and endoplasmic reticulum links with mitochondria. Potential therapeutic strategies may also incorporate exercise, microRNAs, mitochondrial transplantation, stem cell therapies, and photobiomodulation. Despite multiple studies adopting numerous treatment strategies, clinical trials to date have generally failed to show benefit. To overcome this hurdle, more accurate biomarkers of mitochondrial dysfunction are required to detect subtle beneficial effects. Furthermore, selecting study participants early in the disease course, studying them for suitable durations, and stratifying them according to genetic and neuroimaging findings may increase the likelihood of successful clinical trials. Moreover, treatments involving combined approaches will likely better address the complexity of mitochondrial dysfunction in Parkinson's disease. Therefore, selecting the right patients, at the right time, and using targeted combination treatments, may offer the best chance for development of an effective novel therapy targeting mitochondrial dysfunction in Parkinson's disease.

Gene Therapeutic Approaches for the Treatment of Mitochondrial Dysfunction in Parkinson’s Disease

“…In contrast, as a generic term, "mitochondrial dysfunction" oversimplifies the multifaceted nature of mitochondrial biology in health and disease. PD-associated mitochondrial dysfunction presents with a variety of molecular events, including impaired mitochondrial biogenesis, increased release of reactive oxygen species (ROS), defective mitophagy and trafficking, electron transport chains (ETC) dysfunction, variations in mitochondrial dynamics, calcium (Ca2+) imbalance, neuroinflammation, and possible indirect influences on mitochondrial homeostasis from presumably unrelated pathways (e.g., alpha-synuclein deposition) [8]. The centrality of mitochondria in cellular functioning and the convergence of mammalian metabolism on mitochondria suggest that potential therapies must address a complex web of interconnected pathways [9].…”

“…A promising approach can derive from enhanced insights into the individual disease genetics (e.g., by presymptomatic genetic testing or polygenetic risk scoring) [133]. However, blood-or neuroimaging-based assessments of mitochondrial dysfunction can substantially enhance our current understanding of mitochondrial dysfunction's temporal and spatial dynamics in vivo [8]. Current knowledge gaps of essential aspects of mitochondrial biology need to be closed for the rational design of gene therapies.…”

“…PD: Parkinson's disease. The table has been adapted and modified from Prasuhn et al[8].2.1.2. Gene repair and enhancement of nuclear-encoded mitochondrial genes.…”

Resveratrol Treatment in Human Parkin-Mutant Fibroblasts Modulates cAMP and Calcium Homeostasis Regulating the Expression of Mitochondria-Associated Membranes Resident Proteins

“…PARK2 and PARK6, which encode for parkin and PINK1 respectively, are genes responsible of the onset of familial Parkinson's disease (PD) a progressive degenerative disorder of the central nervous system characterized by dopaminergic neurodegeneration in the substantia nigra pars compacta. Several studies in PD models proved hallmarked dysfunctions of mitochondria, in particular, defect of the respiratory chain complex I, which plays a central role in mitochondrial oxidative phosphorylation (OXPHOS) efficiency and capacity [1], depletion of ATP production, increased reactive oxygen species (ROS) and oxidative stress, anomalies in mitochondrial dynamics, trafficking and turnover, dysregulation in calcium homeostasis, and protein misfolding and aggregation [2][3][4][5][6][7][8][9][10].…”

Role of Cleaved PINK1 in Neuronal Development, Synaptogenesis, and Plasticity: Implications for Parkinson’s Disease

“…Also, studies performed in postmortem PD patient brain tissue have shown decreased mitochondrial biomass, bioenergetic capacity, and altered mitochondrial distribution of mitochondria within the cell bodies and neurites ( Schapira et al, 1990 ; Keeney et al, 2006 ; Navarro et al, 2009 ; Mallach et al, 2019 ). Thus, therapies that reverse mitochondrial dysfunction are a promising therapeutic approach; however, various human clinical trials targeting mitochondrial dysfunction in PD have been unsuccessful in reversing the course of disease (e.g., disease progression and motor symptoms) ( Beal et al, 2014 ; Kieburtz et al, 2015 ; Prasuhn et al, 2021 ). Thereby, additional basic science studies that functionally dissect the role of the various mitochondrial localized PD-linked gene products and their function are essential to broaden our understanding of mitochondria and their role in PD pathogenesis, ultimately leading to targeted therapies against PD.…”