Dataset Information

ATP1A3 regulates protein synthesis for mitochondrial stability under heat stress.

ABSTRACT: Pathogenic variants in ATP1A3, the gene encoding the α3 subunit of the Na+/K+-ATPase, cause alternating hemiplegia of childhood (AHC) and related disorders. Impairments in Na+/K+-ATPase activity are associated with the clinical phenotype. However, it remains unclear whether additional mechanisms are involved in the exaggerated symptoms under stressed conditions in patients with AHC. We herein report that the intracellular loop (ICL) of ATP1A3 interacted with RNA-binding proteins, such as Eif4g (encoded by Eif4g1), Pabpc1 and Fmrp (encoded by Fmr1), in mouse Neuro2a cells. Both the siRNA-mediated depletion of Atp1a3 and ectopic expression of the p.R756C variant of human ATP1A3-ICL in Neuro2a cells resulted in excessive phosphorylation of ribosomal protein S6 (encoded by Rps6) and increased susceptibility to heat stress. In agreement with these findings, induced pluripotent stem cells (iPSCs) from a patient with the p.R756C variant were more vulnerable to heat stress than control iPSCs. Neurons established from the patient-derived iPSCs showed lower calcium influxes in responses to stimulation with ATP than those in control iPSCs. These data indicate that inefficient protein synthesis contributes to the progressive and deteriorating phenotypes in patients with the p.R756C variant among a variety of ATP1A3-related disorders.

SUBMITTER: Fujii F

PROVIDER: S-EPMC11247502 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

ATP1A3 regulates protein synthesis for mitochondrial stability under heat stress.

Fujii Fumihiko F Kanemasa Hikaru H Okuzono Sayaka S Setoyama Daiki D Taira Ryoji R Yonemoto Kousuke K Motomura Yoshitomo Y Kato Hiroki H Masuda Keiji K Kato Takahiro A TA Ohga Shouichi S Sakai Yasunari Y

Disease models & mechanisms 20240601 6

Pathogenic variants in ATP1A3, the gene encoding the α3 subunit of the Na+/K+-ATPase, cause alternating hemiplegia of childhood (AHC) and related disorders. Impairments in Na+/K+-ATPase activity are associated with the clinical phenotype. However, it remains unclear whether additional mechanisms are involved in the exaggerated symptoms under stressed conditions in patients with AHC. We herein report that the intracellular loop (ICL) of ATP1A3 interacted with RNA-binding proteins, such as Eif4g ( ...[more]

PMID: 38804677

Similar Datasets

Project description:While satellite cells play a key role in the hypertrophy, repair, and regeneration of skeletal muscles, their response to heat exposure remains poorly understood, particularly in beef cattle. This study aimed to investigate the changes in the transcriptome, proteome, and proliferation capability of bovine satellite cells in response to different levels of heat stress (HS) and exposure times. Satellite cells were isolated from 3-mo-old Holstein bulls (body weight: 77.10 ± 2.02 kg) and subjected to incubation under various temperature conditions: 1) control (38 °C; CON), 2) moderate (39.5 °C; MHS), and extreme (41 °C; EHS) for different durations ranging from 0 to 48 h. Following 3 h of exposure to extreme heat (EHS), satellite cells exhibited significantly increased gene expression and protein abundance of heat shock proteins (HSPs; HSP70, HSP90, HSP20) and paired box gene 7 (Pax7; P < 0.05). HSP27 expression peaked at 3 h of EHS and remained elevated until 24 h of exposure (P < 0.05). In contrast, the expression of myogenic factor 5 (Myf5) and paired box gene 3 (Pax3) was decreased by EHS compared to the control at 3 h of exposure (P < 0.05). Notably, the introduction of HSP27 small interference RNA (siRNA) transfection restored Myf5 expression to control levels, suggesting an association between HSP27 and Myf5 in regulating the self-renewal properties of satellite cells upon heat exposure. Immunoprecipitation experiments further confirmed the direct binding of HSP27 to Myf5, supporting its role as a molecular chaperone for Myf5. Protein-protein docking algorithms predicted a high probability of HSP27-Myf5 interaction as well. These findings indicate that extreme heat exposure intrinsically promotes the accumulation of HSPs and modulates the early myogenic regulatory factors in satellite cells. Moreover, HSP27 acts as a molecular chaperone by binding to Myf5, thereby regulating the division or differentiation of satellite cells in response to HS. The results of this study provide a better understanding of muscle physiology in heat-stressed cells, while unraveling the intricate molecular mechanisms that underlie the HS response in satellite cells.

Dataset Information

ATP1A3 regulates protein synthesis for mitochondrial stability under heat stress.

Publications

ATP1A3 regulates protein synthesis for mitochondrial stability under heat stress.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets