Unveiling the intricacies of mitochondrial pathology: SIAH protein, PINK۱, and Parkinson's Disease

Mitochondrial dysfunction is a central pathological feature of Parkinson’s disease (PD), contributing to dopaminergic neuronal death and progressive motor decline. Among the key regulators of mitochondrial quality control is PINK۱, a serine/threonine kinase that activates mitophagy upon mitochondrial depolarization. However, the role of other mitochondrial-associated E۳ ubiquitin ligases—particularly SIAH۱ (Seven in Absentia Homolog ۱)—in modulating this process remains insufficiently understood. This study aims to elucidate the functional and molecular interplay between SIAH۱ and PINK۱ in the regulation of mitochondrial dynamics and neuronal survival, and to determine their relevance in the context of PD-related pathology. Human SH-SY۵Y and HEK۲۹۳T cells were transfected with SIAH۱ and/or PINK۱ expression vectors to assess mitochondrial membrane potential (Δψm), intracellular reactive oxygen species (ROS) production, and cytotoxicity via LDH release. Protein–protein interactions and subcellular localization were examined using co-immunoprecipitation and confocal microscopy. In vivo, stereotactic injection of adeno-associated viruses encoding shRNA against SIAH۱ was performed in the substantia nigra pars compacta of adult C۵۷BL/۶J mice, followed by behavioral assays and immunohistochemical analysis of tyrosine hydroxylase (TH)-positive neurons. SIAH۱ overexpression in vitro significantly disrupted mitochondrial membrane potential, elevated ROS levels, and induced cellular damage. These effects were mitigated by co-expression of PINK۱. Confocal imaging and co-immunoprecipitation revealed spatial and biochemical colocalization of SIAH۱ and PINK۱ in mitochondrial compartments. Western blotting suggested that PINK۱ enhances mitochondrial localization and stability of SIAH۱, possibly by modulating its degradation. In vivo, SIAH۱ knockdown led to significant motor deficits and a reduction in TH-positive neurons in the substantia nigra. Our findings demonstrate a novel regulatory axis between SIAH۱ and PINK۱ that modulates mitochondrial homeostasis and neuronal viability. The SIAH۱–PINK۱ interaction may represent a crucial mechanism contributing to PD pathogenesis and offers a promising therapeutic target for neuroprotection.

کلیدواژه ها:

Parkinson’s Disease ، Mitochondrial Dysfunction ، PINK۱ ، SIAH۱ ، Neurodegeneration