This new review published in Genes & Diseases by authors from Henan University and the Third Affiliated Hospital of Zhengzhou University provides an integrated framework positioning mitochondrial dysfunction and aging-related cellular changes as central, unifying mechanisms underlying PD pathogenesis.
The review synthesizes evidence demonstrating that mitochondrial dysfunction acts as a pathogenic hub linking genetic mutations, environmental toxins, and age-related decline. In dopaminergic neurons of the substantia nigra, impaired oxidative phosphorylation, reduced ATP production, excessive reactive oxygen species generation, and mitochondrial DNA damage create a self-reinforcing cycle of bioenergetic failure and oxidative stress. The authors highlight how mutations in PD-associated genes such as SNCA , LRRK2 , PINK1 , and Parkin further exacerbate these defects by disrupting mitochondrial dynamics and mitophagy, leading to the accumulation of damaged mitochondria and progressive neuronal loss.
Aging emerges as a critical modifier of these processes. In healthy aging brains, compensatory mechanisms partially preserve mitochondrial DNA and function. In contrast, this adaptive capacity is markedly impaired in PD, resulting in reduced mitochondrial resilience and heightened vulnerability of dopaminergic neurons. The review highlights how age-related declines in antioxidant defenses, calcium homeostasis, and mitochondrial quality control amplify neuronal degeneration and accelerate disease progression.
Importantly, the authors extend the focus beyond neurons to emphasize the role of aging glial cells in PD. Aging microglia exhibit mitochondrial metabolic reprogramming, reduced phagocytic capacity, and a shift toward a pro-inflammatory phenotype driven by pathways such as TREM2 down-regulation and NF-κB/NLRP3 activation. These changes promote neuroinflammation and α-synuclein accumulation, further stressing neuronal mitochondria. In parallel, aging astrocytes undergo mitochondrial dysfunction and senescence mediated by the cGAS–STING–YY1 axis, leading to impaired metabolic support, increased inflammatory signaling, and a neurotoxic microenvironment.
The review also integrates emerging clinical and experimental evidence from postmortem studies, patient-derived cells, and animal models, highlighting both region-specific and systemic mitochondrial abnormalities in PD. These findings underscore the complexity of mitochondrial dysfunction, which can precede overt neurodegeneration and may serve as both a pathogenic driver and a biomarker.
The authors conclude by highlighting therapeutic opportunities that target mitochondrial quality control, redox balance, and neuroinflammatory signaling. They argue that strategies aimed at restoring mitochondrial resilience—particularly in the context of aging—may offer disease-modifying potential. Overall, this review reframes PD as a disorder of mitochondrial aging across interconnected neuronal and glial networks, providing a coherent roadmap for future mechanistic and translational research.
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