Introduction:MondoA is a glucose-sensing transcription factor that regulates glycolytic and metabolic gene expression.While its functions in skeletal muscle and immune cells have been characterized, its role in renal proximal tubular cells remains unclear.We previously reported that proximal tubule-specific MondoA knockout (MondoA-KO) mice show increased susceptibility to acute kidney injury (AKI) and accelerated progression to chronic kidney disease (CKD), accompanied by marked suppression of lipid metabolism.This study aimed to clarify how MondoA regulates energy metabolism and mitochondrial homeostasis in proximal tubular cells and to determine its contribution to renal aging.Methods: MondoA-KO mice and MondoA-deficient proximal tubular cells were analyzed under both normal and fasting conditions.The expression of genes related to lipolysis and lipogenesis was quantified by real-time PCR, and ATP production was measured in vivo and in vitro.Fatty acid oxidation (FAO) activity was assessed using the FAO-Blue assay, while glycolytic activity was assessed using a flux analyzer.Mitochondrial reactive oxygen species (ROS) generation was measured with MitoSOX Red in cultured tubular cells.Glycolytic dependence was examined by treatment with 2-deoxyglucose.Phosphorylation of AMP-activated protein kinase (AMPK) was evaluated as a marker of energy sensing, and rescue experiments were performed by introducing a MondoA overexpression vector.Kidneys from aged knockout mice (up to 24 months) were examined histologically to assess fibrotic and tubular alterations.Results: Starved MondoA-KO mice exhibited impaired lipolysis and lipogenesis, leading to decreased ATP production.MondoA-deficient cells showed reduced FAO but increased glycolysis and ROS levels.Inhibition of glycolysis markedly suppressed cell proliferation, indicating a shift toward glycolytic dependency.AMPK phosphorylation was attenuated in the absence of MondoA but restored by MondoA overexpression.Aged MondoA-KO mice exhibited modest worsening of renal fibrosis and tubular atrophy compared with control mice, consistent with mild acceleration of metabolic aging.Conclusion: MondoA serves as a key metabolic regulator in proximal tubular cells by maintaining lipid metabolism, mitochondrial integrity, and energy balance.Its deficiency impairs AMPK activation, suppresses FAO, increases oxidative stress, and promotes fibrotic and metabolic aging of the kidney.Thus, MondoA protects against metabolic stress and age-related renal deterioration through preservation of energy homeostasis.I have no potential conflict of interest to disclose.I did not use generative AI and AI-assisted technologies in the writing process.
SHAMINI AJIT KUMAR (Wed,) studied this question.