Lipocalin-2 (LCN2) is a secreted protein involved in transporting hydrophobic molecules, regulating antibacterial responses and iron homeostasis. LCN2 expression is induced in response to kidney damage, and participates to chronic kidney disease (CKD) onset. We previously identified LCN2 as a key regulator of mitochondrial dysfunction in renal tubular cells contributing to kidney injury. In this study, we characterized LCN2 interactome to better understand its role in mitochondrial dysfunction and kidney pathology. We identified Clustered Mitochondrial Homolog (CLUH) as protein partner of LCN2. CLUH regulates mitochondrial homeostasis by binding mRNAs of nuclear-encoded mitochondrial proteins and promoting their translation. We demonstrated that LCN2 interaction with CLUH inhibits its activity, leading to mitochondrial clustering around the nucleus. We showed that CLUH is expressed in nephron and that its expression and activity decrease while LCN2 expression increases following kidney injury leading to CKD. In human CKD patients, CLUH expression is inversely correlated with kidney lesions and loss of function. Genetic CLUH deletion in renal tubular cells induces mitochondrial dysfunction, metabolic shift, and oxidative stress ultimately contributing to renal pathology. Our results underscore the critical role of CLUH in maintaining mitochondrial integrity and its interplay with LCN2 in renal disease progression.