Acute kidney injury (AKI) is a prevalent and severe renal disease characterized by high morbidity, mortality, and substantial medical economic burden, emerging as a critical global public health challenge [1,2]. Epidemiological studies reveal that AKI affects millions of patients annually, with incidence rates reaching up to 50 % in intensive care unit patients and mortality rates between 40 % and 60 %, severely threatening patient survival and quality of life [3]. Renal tubular epithelial cells, as key functional units of the kidney, play a crucial role in AKI progression [4]. Mitochondria, as core cellular organelles for energy metabolism and stress response, undergo homeostatic imbalance as one of the critical molecular mechanisms in AKI occurrence and development [5]. Mitochondrial dynamic equilibrium, encompassing complex processes such as fusion, fission, quality control, and biogenesis, is crucial for maintaining normal cellular physiological functions [6,7]. During AKI, mitochondrial dysfunction, dynamic imbalance, and oxidative stress directly lead to renal tubular epithelial cell apoptosis and necrosis, thereby exacerbating kidney injury [8,9].

In recent years, the significant role of molecular chaperone protein families in regulating mitochondrial homeostasis and cellular stress has attracted widespread research attention [10]. DNAJC6, a heat shock protein co-chaperone, plays a crucial regulatory role in multiple disease developments [11,12]. In 2012, Elpeleg et al. revealed that the DNAJC6 gene encodes auxilin, a neuron-specific auxiliary protein involved in uncoating clathrin-coated proteins from cellular membrane transport vesicles [13]. DNAJC6 mutations are associated with juvenile Parkinson's disease. Existing research primarily focused on DNAJC6's roles in neurodegenerative diseases and tumors [14,15], but its specific molecular mechanisms in AKI remain unclear. Peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), as a critical transcriptional coactivator, plays a core role in regulating mitochondrial biogenesis, energy metabolism, and antioxidant responses [16]. Previous studies have demonstrated that PGC-1α can maintain mitochondrial functional homeostasis by regulating the expression of multiple key mitochondria-related genes, which is crucial for resisting cellular stress damage [17,18]. Recent research indicates that PGC-1α is a key transcriptional coactivator in mitochondrial biogenesis and energy metabolism regulation [19,20]. Spiegelman's team confirmed in a 2005 study that PGC-1α directly influences mitochondrial function and cellular energy metabolism by regulating mitochondrial respiratory chain complex expression [21]. However, whether DNAJC6 participates in AKI progression by modulating PGC-1α remains unknown.

This study aimed to elucidate the expression pattern changes of DNAJC6 in renal tubular epithelial cells. Furthermore, we sought to clarify the impact of DNAJC6 on mitochondrial function and cell survival in renal tubular epithelial cells and provide an in-depth analysis of the molecular mechanism by which DNAJC6 regulates PGC-1α and its protective role in AKI. We investigated the potential regulatory mechanism of the DNAJC6-PGC-1α axis on mitochondrial dynamic equilibrium and antioxidant response. Our objective was to delineate the molecular mechanism by which DNAJC6 protects renal tubular epithelial cells through PGC-1α-mediated mitochondrial homeostasis in AKI. The scientific significance of this research lies in revealing the molecular mechanism by which DNAJC6 regulates mitochondrial homeostasis through PGC-1α, providing a novel theoretical foundation for understanding AKI pathogenesis. From a clinical perspective, this study is expected to offer potential molecular targets and therapeutic strategies for precise AKI treatment, improving patient outcomes. The research findings will provide crucial theoretical basis and practical guidance for treating mitochondrial dysfunction-related diseases.