Takatori, M. | Search bioRxiv

bioRxiv2026

IF1 restrains excessive elevation of the mitochondrial membrane potential and safeguards the epithelial state of human induced pluripotent stem cells

Human pluripotent stem cells (hPSCs) rely on glycolysis and exhibit low mitochondrial respiration, conditions under which F1Fo ATP synthase tends to run in reverse, hydrolyzing ATP. ATP synthase inhibitory factor subunit 1 (IF1) inhibits F1Fo-mediated ATP hydrolysis, but its significance in glycolytic hPSCs remains unclear. Here, we show that stable IF1 knockdown (IF1-KD) in human induced pluripotent stem cells (hiPSCs) enhanced mitochondrial ATP hydrolysis and elevated the mitochondrial membrane potential ({Delta}{Psi}m). Markers of the undifferentiated state were largely maintained, whereas IF1-KD cells exhibited reduced epithelial characteristics and a partial epithelial-mesenchymal transition (EMT)-like state. IF1-KD cells also showed enhanced store-operated Ca2 entry (SOCE) and increased nuclear NFATc3. Pharmacological reduction of {Delta}{Psi}m attenuated SOCE, whereas NFATc3 overexpression reproduced key features of the EMT-like expression pattern. Endogenous IF1 therefore acts as a constitutive restraint on reverse-mode F1Fo activity, limiting excessive {Delta}{Psi}m and downstream SOCE-NFATc3 signaling and safeguarding the epithelial state of hPSCs.

Cell Biology↗

bioRxiv2024

Viral antigen mismatch affects antiviral T-cell response and may impair immunotherapeutic efficacy against ATL

Human T-cell leukemia virus type 1 (HTLV-1) has the potential to transform primary CD4+ T cells in vitro within a short time; however, the majority of infected individuals maintain an asymptomatic and disease-free condition, suggesting the existence of an equilibrium between the proliferation of infected cells and host immunity. The decline in anti-viral immunity contributes to the transformation of the infected cells, leading to the development of adult T-cell leukemia/lymphoma (ATL). This study identified a variation in a major viral antigen, HTLV-1 Tax, in human leukocyte antigen-A24 (HLA-A24) positive individuals. Two variants of Tax301-309 peptides, SFHNLHLLF (Tax301-309 A) and SFHSLHLLF (Tax301-309 B) were found to induce distinct T-cell immune responses in HLA-A24 positive individuals. There was a disparity between two Tax301-309 peptides in the detection of anti-Tax301-309 cytotoxic T-lymphocytes (CTLs) binding to A24/peptide multimers by flow cytometry analysis. More importantly, over half of the anti-Tax TCRs of anti-Tax CTLs from infected individuals did not recognize mismatched Tax301-309 peptides by Enzyme-Linked Immunospot (ELISpot) assay using Jurkat T cells expressing the anti-Tax301-309 specific TCR. These findings underscore the importance of matching the viral antigen epitope type in T-cell-based immunotherapy against ATL by using viral antigen Tax. Key pointsO_LIEpitope heterogeneity in the major viral antigen in HTLV-1 infection causes different T-cell responses in infected individuals. C_LIO_LIRecommended guideline; performing virus typing to obtain optimal efficacy in T-cell-mediated immunotherapy against the viral antigen Tax C_LI

immunology↗