MICU1 deficiency exacerbates cisplatin-induced acute kidney injury by tubular apoptosis and mitochondrial dysfunction.

Cisplatin-induced acute kidney injury (AKI) is characterized by profound oxidative stress and mitochondrial dysfunction in proximal tubular cells. However, the upstream mechanisms governing this redox imbalance remain incompletely defined. Here, we identify mitochondrial calcium uptake 1 (MICU1) as a critical regulator of tubular redox homeostasis. Using integrated multi-omics approaches, we found that MICU1 is markedly downregulated in injured proximal tubular subpopulations across various kidney diseases. Mechanistically, MICU1 deficiency disrupts mitochondrial calcium homeostasis, resulting in calcium overload and excessive mitochondrial reactive oxygen species (mtROS) generation. These changes trigger intrinsic apoptotic pathways, whereas MICU1 restoration alleviates such damage. Furthermore, we demonstrate that the ARNT/HIF-1α axis transcriptionally regulates MICU1. Under cisplatin stress, this axis is suppressed, thereby promoting mitochondrial dysfunction. Crucially, we found that MICU1-mediated mtROS control contributes to the preservation of epidermal growth factor receptor (EGFR) signaling, whereas excessive mtROS accumulation is associated with EGFR signaling impairment. Importantly, pharmacological targeting of mitochondrial calcium uptake using the small-molecule modulator MCU-i4 attenuates calcium overload, suppresses mtROS accumulation, and mitigates renal injury in vitro and in vivo. Collectively, our findings support a transcriptional-mitochondrial axis linking calcium dysregulation to oxidative stress and identify MICU1 as a potential therapeutic target for redox-driven kidney injury.