Molecular mechanisms of mitochondrial dysfunction in PD. (IMAGE)
Caption
(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.
Credit
Tingting Liu, Jingwen Li, Haojie Wu, Junbo Qiao, Jianshe Wei
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