Mitochondria and aging: A central axis in Parkinson’s disease pathogenesis

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.

Reference
Title of Original Paper: Unraveling Parkinson's disease: The mystery of mitochondria and the role of aging

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101719

Funding Information:

The National Natural Science Foundation of China (No. 32161143021, No. 81271410)
Henan University graduate “Talent Program” of Henan Province, China (SYLYC2023092)
Henan Natural Science Foundation of China (No. 182300410313)
Key Research and Development Project of Henan Province, China (No. 231111311400)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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Attached files

Affected brain regions and pathogenic factors of PD. (A) In early/mid-stage PD, the nigrostriatal pathway (indicated by red arrow) is primarily affected, leading to impaired voluntary movement control due to dopamine depletion in the striatum. During late-stage PD, three additional pathways are compromised: the mesocortical pathway (green arrow), associated with cognitive functions such as memory and motivation; the mesolimbic pathway (blue arrow), involved in emotional processing and reward perception; and the tubero-infundibular pathway (purple arrow), which regulates hormonal balance and sensory integration. (B) The pathogenesis of PD involves three major factors: (1) aging, which accelerates mitochondrial dysfunction (2) environmental toxins (e.g., pesticides, heavy metals) that inhibit mitochondrial complex I and induce oxidative stress; and (3) genetic mutations (e.g., SNCA, LRRK2, PINK1, and Parkin) that disrupt mitochondrial quality control and autophagy. (C) The cascade of neuronal damage begins with dopaminergic neuron degeneration in the substantia nigra, causing insufficient dopamine secretion. Mitochondrial dysfunction exacerbates this process by reducing ATP production and amplifying oxidative stress, creating a vicious cycle that further damages neurons and drives disease progression.
Molecular mechanisms of mitochondrial dysfunction in PD. (1) Imbalances in mitochondrial dynamics, where excessive fission (mediated by Fis1/Drp1) and impaired fusion disrupt organelle integrity; (2) impaired autophagy, evidenced by defective PINK1/Parkin-mediated mitophagy, leading to the accumulation of damaged mitochondria; (3) oxidative stress, manifested through respiratory chain damage (NADH/CoQ dysfunction), mtDNA mutations, and lipid/protein oxidation; (4) energy metabolism collapse, with reduced ATP production due to OXPHOS defects in both neurons and muscle; and (5) calcium dyshomeostasis, driven by LRRK2/PINK1 mutations and STAT-PIAS2 pathway disruption, which further exacerbates mitochondrial swelling and neuronal excitotoxicity. These interconnected mechanisms converge on dopaminergic neuron degeneration in the substantia nigra, while muscle-specific OXPHOS deficits (e.g., enzyme complex I/III reduction) contribute to systemic PD pathology. The JAK-STAT-PIAS2 axis and IFNβ-IFNAR signaling are highlighted as modulators of neuronal survival and inflammatory responses.
Aging exacerbates PD pathology through mitochondrial dysfunction and neuroinflammation (1) Mitochondrial failure, where aging reduces compensatory mtDNA replication, leads to ROS accumulation, respiratory chain damage (NADH/CoQ deficiency), and membrane potential collapse. These defects impair ATP production while increasing oxidative damage to lipids/proteins. (2) α-Synuclein aggregation is amplified by aging microglia through TREM2 down-regulation and TLR/NF-κB/NLRP3 activation, which promotes the release of inflammatory factor (e.g., IL-1β and TNF-α) and JNK/AP-1 pathway-mediated neuronal stress. (3) Astrocyte senescence, driven by the cGAS–STING–IRF3 axis and LCN2 up-regulation, creates a neurotoxic environment via endoplasmic reticulum stress and diminished antioxidant defenses (SOD/GPx/GSH depletion). Collectively, these processes form a vicious cycle: mitochondrial OXPHOS fragmentation and calcium dyshomeostasis accelerate neuronal damage, while microglial/astrocytic inflammation further propagates α-synuclein pathology, ultimately driving dopaminergic neurodegeneration

19/02/2026 Compuscript Ltd

Regions: Europe, Ireland, Asia, China

Keywords: Science, Life Sciences

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