Compensatory Mitophagy via NEDD4/HIF-1α/BNIP3 Pathway Restrains EndMT and Renal Allograft Interstitial Fibrosis Induced by TNFα.

Renal allograft interstitial fibrosis/tubular atrophy (IF/TA) is the pathological hallmark of chronic renal allograft dysfunction (CAD) and endothelial-to-mesenchymal transition (EndMT) has been implicated as one of the key triggering factors. Here, we identified tumor necrosis factor-α (TNFα) as a key inducer of mitochondrial dysfunction and EndMT in endothelial cells of renal allografts. Importantly, TNFα simultaneously activated BNIP3-dependent mitophagy as a compensatory response, which removed damaged mitochondria, restrained EndMT, and attenuated renal allograft interstitial fibrosis. In addition, inhibition of BNIP3 promoted the accumulation of damaged mitochondria, aggravated EndMT, and exacerbated renal allograft interstitial fibrosis, supporting a protective role of mitophagy. Mechanistically, TNFα upregulated and stabilized HIF-1α by disrupting its NEDD4-mediated ubiquitination, thereby enhancing BNIP3 transcription to drive mitophagy. Moreover, endothelial-specific deletion of HIF-1α impaired this compensatory pathway, aggravated mitochondrial dysfunction, and exacerbated renal allograft interstitial fibrosis. Thus, compensatory mitophagy through the NEDD4/HIF-1α/BNIP3 pathway represented a potential protective stress-adaptation program in renal allograft endothelial cells, providing mechanistic insight and a conceptual framework for future therapeutic exploration aimed at preserving renal allograft function.