Atp5f1d-KO Mouse

ATP5F1D, formerly known as ATP5D, is a subunit of ATP synthase, a crucial component of the mitochondrial electron transport chain (ETC). It plays a vital role in coupling proton translocation and ATP production, thereby being essential for cellular energy metabolism [3]. The ETC is involved in numerous biological processes and is linked to carcinogenesis [1,2]. Genetic models, such as gene knockdown in Drosophila or cell-line based loss-of-function assays in mammals, can help in understanding its functions.

In endometrial cancer (EC), ATP5F1D expression is upregulated and associated with a favorable prognosis. Knockdown of ATP5F1D in EC cell lines (KLE and Ishikawa) inhibits cell proliferation, invasion, and migration. In vivo, in a nude mouse model of human endometrial tumor, ATP5F1D knockdown suppressed tumor growth. The mechanism involves a decrease in mitochondrial ROS (mtROS) production and inhibition of pyroptosis via the mtROS/NLRP3/caspase-1/GSDMD pathway [1]. Additionally, in the context of EC, ATP5F1D has high diagnostic value, is related to tumor immune infiltration, and EC patients with high ATP5F1D expression have better immune treatment responses and chemotherapy sensitivity [2]. In spermatozoa from patients with repetitive fertilization failure after ICSI, altered abundance of ATP5F1D was observed, indicating its potential role in fertilization-related mitochondrial function [4]. Biallelic mutations in ATP5F1D in humans lead to a metabolic disorder, with impaired assembly of F1FO ATP synthase and reduced complex V activity in cultured skin fibroblasts [3].

In summary, ATP5F1D is essential for mitochondrial ATP production and energy metabolism. Model-based research, including loss-of-function experiments in cell lines and animal models, has revealed its significance in endometrial cancer progression, immune response in the context of EC, sperm function related to fertilization, and a Mendelian mitochondrial disease. Understanding ATP5F1D's functions provides insights into these biological processes and disease conditions, potentially guiding future therapeutic strategies [1,2,3,4].

References:

1. Cheng, Yuemei, Chen, Xi, Hu, Dan, Liang, Xiaolei, Yang, Yongxiu. 2024. Downregulation of ATP5F1D inhibits mtROS/NLRP3/caspase-1/GSDMD axis to suppress pyroptosis-mediated malignant progression of endometrial cancer. In International immunopharmacology, 139, 112808. doi:10.1016/j.intimp.2024.112808. https://pubmed.ncbi.nlm.nih.gov/39079199/

2. Cheng, Yuemei, Liang, Xiaolei, Bi, Xuehan, Liu, Chang, Yang, Yongxiu. 2024. Identification ATP5F1D as a Biomarker Linked to Diagnosis, Prognosis, and Immune Infiltration in Endometrial Cancer Based on Data-Independent Acquisition (DIA) Analysis. In Biochemical genetics, 62, 4215-4236. doi:10.1007/s10528-023-10646-9. https://pubmed.ncbi.nlm.nih.gov/38265620/

3. Oláhová, Monika, Yoon, Wan Hee, Thompson, Kyle, Bernstein, Jonathan A, Wheeler, Matthew T. 2018. Biallelic Mutations in ATP5F1D, which Encodes a Subunit of ATP Synthase, Cause a Metabolic Disorder. In American journal of human genetics, 102, 494-504. doi:10.1016/j.ajhg.2018.01.020. https://pubmed.ncbi.nlm.nih.gov/29478781/

4. Torra-Massana, Marc, Jodar, Meritxell, Barragán, Montserrat, Oliva, Rafael, Vassena, Rita. 2021. Altered mitochondrial function in spermatozoa from patients with repetitive fertilization failure after ICSI revealed by proteomics. In Andrology, 9, 1192-1204. doi:10.1111/andr.12991. https://pubmed.ncbi.nlm.nih.gov/33615715/