Atp5f1b, also known as ATP synthase F1 subunit beta, is a subunit of the mitochondrial ATP synthase or complex V of the mitochondrial respiratory chain. This complex is crucial for oxidative phosphorylation, a process that generates ATP, the cell's energy currency. Mitochondrial function is essential for various biological processes, and thus Atp5f1b is of great biological importance [1,2,3,4,5,6,7,8].

Pathogenic variants in Atp5f1b have been identified. In two families, missense variants in Atp5f1b segregated with early-onset isolated dystonia, showing an autosomal dominant mode of inheritance with incomplete penetrance. Functional studies in mutant fibroblasts revealed a severe reduction of complex V activity and impaired mitochondrial membrane potential despite no decrease in Atp5f1B protein amount, suggesting a dominant-negative effect [1]. Additionally, a de novo heterozygous variant in Atp5f1b was found in identical twin boys with congenital hypermetabolism. Expression of the mutant allele in human cell lines recapitulated the phenotype of elevated oxygen consumption and decreased mitochondrial membrane potential, indicating an autosomal dominant mitochondrial uncoupling syndrome with hypermetabolism [5]. A Mendelian randomization analysis also showed a positive causal relationship between Atp5f1b and diabetic ketoacidosis, suggesting that excessive ATP production related to Atp5f1b in diabetic patients may increase the risk of this severe complication [7].

In conclusion, Atp5f1b is vital for mitochondrial ATP synthesis. Studies on Atp5f1b-related variants in human subjects have revealed its role in conditions such as isolated dystonia, congenital hypermetabolism, and diabetic ketoacidosis. These findings contribute to understanding the molecular mechanisms underlying these diseases and may potentially lead to new therapeutic strategies.

References:

1. Nasca, Alessia, Mencacci, Niccolò E, Invernizzi, Federica, Garavaglia, Barbara, Ghezzi, Daniele. . Variants in ATP5F1B are associated with dominantly inherited dystonia. In Brain : a journal of neurology, 146, 2730-2738. doi:10.1093/brain/awad068. https://pubmed.ncbi.nlm.nih.gov/36860166/

2. Zhang, Tai-Mei, Liao, Li, Yang, Shao-Ying, Shao, Zhi-Min, Li, Da-Qiang. 2022. TOLLIP-mediated autophagic degradation pathway links the VCP-TMEM63A-DERL1 signaling axis to triple-negative breast cancer progression. In Autophagy, 19, 805-821. doi:10.1080/15548627.2022.2103992. https://pubmed.ncbi.nlm.nih.gov/35920704/

3. Ponsford, Amy H, Ryan, Thomas A, Raimondi, Andrea, Swan, Laura E, Stagi, Massimiliano. 2020. Live imaging of intra-lysosome pH in cell lines and primary neuronal culture using a novel genetically encoded biosensor. In Autophagy, 17, 1500-1518. doi:10.1080/15548627.2020.1771858. https://pubmed.ncbi.nlm.nih.gov/32515674/

4. Wauters, Fieke, Cornelissen, Tom, Imberechts, Dorien, Vangheluwe, Peter, Vandenberghe, Wim. 2019. LRRK2 mutations impair depolarization-induced mitophagy through inhibition of mitochondrial accumulation of RAB10. In Autophagy, 16, 203-222. doi:10.1080/15548627.2019.1603548. https://pubmed.ncbi.nlm.nih.gov/30945962/

5. Ganetzky, Rebecca D, Markhard, Andrew L, Yee, Irene, To, Tsz-Leung, Mootha, Vamsi K. . Congenital Hypermetabolism and Uncoupled Oxidative Phosphorylation. In The New England journal of medicine, 387, 1395-1403. doi:10.1056/NEJMoa2202949. https://pubmed.ncbi.nlm.nih.gov/36239646/

6. Hu, Chenxi, Zheng, Zaosong, Pang, Shiyu, Wang, Qiong, Tan, Wanlong. 2024. Chimeric SFT2D2-TBX19 Promotes Prostate Cancer Progression by Encoding TBX19-202 Protein and Stabilizing Mitochondrial ATP Synthase through ATP5F1A Phosphorylation. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2408426. doi:10.1002/advs.202408426. https://pubmed.ncbi.nlm.nih.gov/39540264/

7. Xie, Ruiqiang, Xie, Hongyan, Gao, Hong, Yuan, Haipo, Feng, Zhijun. 2024. Mitochondrial proteins as therapeutic targets in diabetic ketoacidosis: evidence from Mendelian randomization analysis. In Frontiers in pharmacology, 15, 1448505. doi:10.3389/fphar.2024.1448505. https://pubmed.ncbi.nlm.nih.gov/39469619/

8. Zhiyan, Chen, Min, Zhan, Yida, Du, Huan, Wang, Linjuan, Sun. 2024. Bioinformatic analysis of hippocampal histopathology in Alzheimer's disease and the therapeutic effects of active components of traditional Chinese medicine. In Frontiers in pharmacology, 15, 1424803. doi:10.3389/fphar.2024.1424803. https://pubmed.ncbi.nlm.nih.gov/39221152/