PINK1

What is PINK1 protein?

PINK1 gene (PTEN induced kinase 1) is a protein coding gene which situated on the short arm of chromosome 1 at locus 1p36. PINK1 protein is a serine/threonine protein kinase that plays a crucial role in mitochondrial quality control. PINK1 plays an important role in maintaining mitochondrial health and function, especially during the identification and clearance of damaged mitochondria. When mitochondrial function is impaired or membrane potential is decreased, the accumulation of PINK1 on the damaged mitochondria increases, which in turn activates the E3 ubiquitin ligase Parkin, triggering the process of mitochondrial autophagy, that is, selective clearance of the damaged mitochondria. This function of PINK1 is essential to prevent the development of diseases associated with mitochondrial dysfunction, such as Parkinson's disease. Mutations in PINK1 protein have been linked to early-onset Parkinson's disease, further underscoring its importance in neurodegenerative diseases. The PINK1 protein is consisted of 581 amino acids and PINK1 molecular weight is approximately 62.8 kDa.

What is the function of PINK1 protein?

PINK1 protein is a mitochondrial protein kinase whose main function is to maintain mitochondrial quality control and maintain cell health by promoting autophagy of damaged mitochondria. It accumulates when the mitochondrial membrane potential declines and activates Parkin, initiating the process of mitochondrial autophagy, thereby clearing the dysfunctional mitochondria. In addition, PINK1 is also involved in the regulation of mitochondrial dynamics, antioxidant stress response, and cell death pathways, which has an important impact on the occurrence and development of neurodegenerative diseases such as Parkinson's disease.

Fig1. Impact of PINK1 deficiency in neural cells. (Elvira Pequeno Leites, 2021)

PINK1 related signaling pathway

The primary function of PINK1 is to maintain a healthy state of mitochondria through its kinase activity. When mitochondrial function is impaired or membrane potential is decreased, the accumulation of PINK1 on the damaged mitochondria increases, which in turn activates the E3 ubiquitin ligase Parkin. This process triggers mitophagy, the process of selectively removing damaged mitochondria, which is critical for cell health and preventing diseases associated with mitochondrial dysfunction. The activation mechanism of PINK1 involves its maturation on mitochondria, autophosphorylation, and interaction with Parkin. PINK1 phosphorylates ubiquitin, a step that is critical for the activation of Parkin.

PINK1 related diseases

PINK1 protein has been implicated in a variety of diseases, especially in the pathogenesis of Parkinson's disease (PD). Mutations in the PINK1 gene are one of the known causes of autosomal recessive early onset Parkinson's disease. In addition to Parkinson's disease, abnormal function of PINK1 has also been linked to other diseases, including neonatal hypoxic ischemic encephalopathy, certain types of tumors (such as glioma and breast cancer), and diabetes. The role of PINK1 in these diseases may involve many aspects such as mitochondrial function, apoptosis, cell cycle regulation and cell metabolism.

Bioapplications of PINK1

As a key regulator of mitochondrial quality control, rhPINK1 can be utilized to restore mitochondrial function in diseases associated with mitochondrial dysfunction, such as Parkinson's disease. By phosphorylating parkin, it facilitates the removal of damaged mitochondria through mitophagy, thereby enhancing cellular energy metabolism and reducing oxidative stress. This therapeutic potential extends to other neurodegenerative disorders and conditions characterized by mitochondrial impairment. Additionally, its role in promoting cell survival and reducing apoptosis makes it a candidate for interventions aimed at improving cardiac function following ischemic injury or in models of heart failure.

Case Study 1: Zhenxing Si, 2023

Osteosarcoma, a prevalent bone cancer in young people, has unknown links to PINK1, a protein known for its role in Parkinson's disease. This study aimed to explore PINK1's impact on osteosarcoma using bioinformatics and cell-based assays. They discovered that elevated PINK1 levels correlated with worse outcomes and were associated with reduced apoptosis and increased cell proliferation. PINK1 was overexpressed in osteosarcoma tissues, and its suppression decreased cell growth and proliferation in U2OS cells, as shown by CCK-8 and Ki67 staining. Apoptosis was induced by PINK1 knockdown, as evidenced by increased cleaved caspase-3 levels. Cisplatin's pro-apoptotic effect in osteosarcoma cells was partly due to PINK1 downregulation.

Fig1. Depletion of FOXO3a suppressed PINK1 expression.

Fig2. Western blot was assessed to compare PINK1 expression in U2OS cells before and after Cisplatin treatment.

Case Study 2: Fabienne C Fiesel, 2023

The PINK1-PRKN complex is crucial for mitophagy, the selective degradation of damaged mitochondria, and is implicated in Parkinson's disease (PD). While enhancing this pathway is therapeutically promising, its benefits are not universally established. This study investigated the effects of PINK1 variants on mitophagy using biochemical and cell biology techniques. The PINK1G411A variant, unlike the PD-associated PINK1G411S mutation which reduces kinase activity, significantly increased ubiquitin phosphorylation. This led to enhanced PRKN activation, mitophagy, and improved neuron viability post-mitochondrial stress. The G411A variant stabilizes PINK1's kinase structure, facilitating a conformation in ubiquitin that favors substrate processing.

Fig3. Quantification of phosphorylated PINK1.

Fig4. Mitochondria from HEK293T WT PINK1 (labeled G) and PINK1G411A (labeled A) cells were used for kinase reactions

PINK1 has several biochemical functions, for example, ATP binding,C3HC4-type RING finger domain binding,calcium-dependent protein kinase activity. Some of the functions are cooperated with other proteins, some of the functions could acted by PINK1 itself. We selected most functions PINK1 had, and list some proteins which have the same functions with PINK1. You can find most of the proteins on our site.

PINK1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with PINK1 here. Most of them are supplied by our site. Hope this information will be useful for your research of PINK1.

PARK2;EED;FBXO7