Atp5if1, encoding ATPase Inhibitory Factor 1 (IF1), is the physiological inhibitor of mitochondrial ATP synthase. It plays a crucial role in regulating mitochondrial energy metabolism and is involved in pathways such as oxidative phosphorylation. Its function is of great biological importance as it impacts various cellular processes related to energy production and cell function [1,2,3,4]. Genetic models, like gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying Atp5if1's role.

In conditional CD4+-IF1-knockout mice, T lymphocytes show impaired glucose uptake, reduced glycolysis flux, decreased mitochondrial biogenesis, and compromised cellular proliferation after activation. These mice cannot mount an effective Th1 response against bacterial infection, highlighting Atp5if1's essential role in adaptive immune responses [1]. In acute myeloid leukemia (AML), down-regulation of ATP5IF1 in AML cells made refractory to venetoclax enhances mitochondrial ATP consumption, conferring drug resistance. Knockdown of ATP5IF1 also confers venetoclax resistance, while its overexpression heightens sensitivity to venetoclax, indicating its role in AML's bioenergetic vulnerability [3,5].

In conclusion, Atp5if1 is essential for regulating metabolic reprogramming and functionality in T cells, influencing adaptive immune responses. In AML, it impacts the bioenergetic state of cancer cells and their response to chemotherapy. The study of Atp5if1 using KO/CKO mouse models has provided valuable insights into these disease-related biological processes, helping us better understand the underlying mechanisms and potentially paving the way for new therapeutic strategies.