Dguok, short for deoxyguanosine kinase, is a key nuclear-encoded protein involved in maintaining the mitochondrial DNA (mtDNA) nucleotide pool. The balanced supply of nucleotides by Dguok is crucial for mtDNA synthesis, which is essential for normal mitochondrial function and energy production in cells [4].

Mutations in DGUOK can lead to mitochondrial DNA depletion syndrome (MDS). In MDS patients with DGUOK mutations, there is a high prevalence of iron overload that progresses to severe liver failure. Cellular models derived from patient-specific induced pluripotent stem cells (iPSCs) show that DGUOK mutant hepatocyte-like cells (iHep) and hepatocyte organoids (iHep-Orgs) are more sensitive to iron overload-induced ferroptosis, a process mediated by nuclear receptor co-activator 4 (NCOA4)-dependent degradation of ferritin in lysosome and cellular labile iron release [1]. DGUOK deficiency often leads to early-onset liver failure with concomitant neurological deterioration, and prognosis is generally poor. Some children may also present with nervous system manifestations, along with abnormal laboratory results such as abnormal liver function, increased blood lactate, serum ferritin, and alpha-fetoprotein, and hypoglycemia [2,3]. Additionally, DGUOK variants have been associated with idiopathic non-cirrhotic portal hypertension in children [5].

In conclusion, Dguok is vital for maintaining the mitochondrial nucleotide pool and normal mtDNA synthesis. Studies using cellular models derived from patient iPSCs have revealed its role in the pathophysiology of MDS, especially in relation to iron-related liver damage. Understanding Dguok's function provides insights into the mechanisms of mitochondrial-related liver and neurological diseases, which may guide the development of therapeutic strategies.

References:

1. Guo, Jingyi, Duan, Lifan, He, Xueying, Hu, Huili, Liu, Xingguo. 2021. A Combined Model of Human iPSC-Derived Liver Organoids and Hepatocytes Reveals Ferroptosis in DGUOK Mutant mtDNA Depletion Syndrome. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 8, 2004680. doi:10.1002/advs.202004680. https://pubmed.ncbi.nlm.nih.gov/34026460/

2. Jankowska, Irena, Czubkowski, Piotr, Rokicki, Dariusz, Pawłowska, Joanna, Socha, Piotr. 2020. Acute liver failure due to DGUOK deficiency-is liver transplantation justified? In Clinics and research in hepatology and gastroenterology, 45, 101408. doi:10.1016/j.clinre.2020.02.018. https://pubmed.ncbi.nlm.nih.gov/32278775/

3. Lin, Gui-Zhi, Qiu, Jian-Wu, Deng, Mei, Guo, Li, Song, Yuan-Zong. . [DGUOK-related mitochondrial DNA depletion syndrome: a case report and literature review]. In Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics, 22, 274-279. doi:. https://pubmed.ncbi.nlm.nih.gov/32204766/

4. El-Hattab, Ayman W, Craigen, William J, Scaglia, Fernando. 2017. Mitochondrial DNA maintenance defects. In Biochimica et biophysica acta. Molecular basis of disease, 1863, 1539-1555. doi:10.1016/j.bbadis.2017.02.017. https://pubmed.ncbi.nlm.nih.gov/28215579/

5. Li, Jia-Qi, Feng, Jia-Yan, Gong, Ying, Li, Wang-Qiang, Liu, Teng. 2023. Case report: Novel DGUOK variants associated with idiopathic non-cirrhotic portal hypertension in a Han Chinese child. In Frontiers in pediatrics, 11, 1236239. doi:10.3389/fped.2023.1236239. https://pubmed.ncbi.nlm.nih.gov/37830057/