Age-related macular degeneration (AMD) is one of the leading causes of vision impairment and blindness in the elderly worldwide, with its prevalence increasing significantly with age. The pathogenesis of AMD is multifactorial, involving genetic predisposition, environmental risk factors, chronic inflammation, and mitochondrial dysfunction. In recent years, mitophagy has emerged as a critical mechanism for maintaining mitochondrial quality control, energy homeostasis, and cellular integrity in retinal pigment epithelium (RPE) and photoreceptor cells. Dysregulated mitophagy leads to the accumulation of damaged mitochondria, excessive reactive oxygen species, and metabolic imbalance, thereby triggering RPE dysfunction, inflammatory amplification, and choroidal neovascularization, which drive AMD progression. Both classical pathways (e.g., PINK1/Parkin) and non-classical pathways (e.g., BNIP3, FUNDC1) have been implicated in AMD pathophysiology. Molecules such as Parkin and p62, as well as multimodal imaging features, hold promise as early biomarkers for disease monitoring. Preclinical studies have shown that small-molecule activators (e.g., Urolithin A, Spermidine) and mitochondria-targeted antioxidants (e.g., MitoQ, SkQ1) can restore mitophagy and alleviate RPE damage. However, current evidence remains limited, as large-scale, long-term clinical trials are lacking. Challenges in drug delivery efficiency, safety, patient stratification, and clinical monitoring tools still hinder translation into practice. Future research should focus on biomarker-driven precision interventions, multicenter randomized controlled trials, and individualized therapeutic strategies. Overall, mitophagy research is transitioning from mechanistic exploration to clinical translation, with promising potential to enable early diagnosis, disease stratification, and precision management of AMD.
PTEN-induced putative kinase 1 (PINK1), a Parkinson's disease (PD)-related protein, has two isoforms, the mitochondria-localized full-length isoform PINK1FL and the cytoplasm-localized short isoform PINK1-cyto. Studies have suggested that PINK1FL can selectively accumulate at the surface of damaged mitochondria and cooperate with another Parkinson's Disease-related protein PARKIN to trigger the degradation of MIRO1, a mitochondria trafficking regulator. The functions of PINK1-cyto are, however, not yet clear. To investigate the functions of PINK1-cyto, we expressed different proteins in cultured HEK293 cells by transfecting it with different plasmids, and detected the protein levels by Western blot after expressing for 24 h. We found that in cultured HEK293 cells, PINK1-cyto could also cooperate with PARKIN degrade MIRO1 in the presence of CK2β, and the regulatory subunit of Casein Kinase Ⅱ. Interestingly, this function of CK2β was not dependent on CK2α, the catalytic subunit of Casein Kinase II. We also found that CK2β could promote the direct interaction between PINK1-cyto and MIRO1 by immunocoprecipitation analysis. This result suggested that in addition to CK2α, CK2β could also form a kinase complex with PINK1-cyto with important physiological functions.
The aim of this study is to determine the regulatory mechanism of PTEN-induced putative kinase protein 1 short isoform (PINK1S) in cytoplasm. By co-immunoprecipitation (Co-IP) assay, we identified that PINK1S interacted with the beta regulatory subunit of Casein Kinase 2 (CK2β), but not with the catalytic subunits CK2α1 and CK2α2. Furthermore, cells were transfected with PINK1S and CK2β, and then PINK1S was purified by immunoprecipitation. After detecting the phosphorylated proteins by Phos-tagTM Biotin, we found that CK2β overexpression increased auto-phosphorylation of PINK1S. Finally, we generated CK2β knockdown cell lines by RNA interference. Purified PINK1S from CK2β knockdown cells significantly reduced its auto-phosphorylation compared with control cells. These results suggested that CK2β functions as a regulatory subunit of PINK1S kinase complex promoted its activation by self-phosphorylation.