This study demonstrated that, in addition to the known metabolic effects of fructose, excessive fructose directly binds to the translocase of the outer membrane (TOM) complex via non-covalent interaction with TOM22, inducing subtle but functionally critical conformational changes in the TOM complex. These changes markedly inhibit the transport of mitochondrial ribosome subunits, impair mitochondrial protein translation, and disrupt oxidative phosphorylation, independent of fructose metabolism. Using both fructose-exposed podocytes and mouse glomerular injury models, the authors further showed that disrupting the fructose-TOM22 interaction restores mitochondrial ribosome subunit trafficking and prevents mitochondrial and oxidative phosphorylation dysfunction, thereby revealing a previously unrecognized, metabolism-independent pathogenic mechanism by which fructose directly remodels a mitochondrial protein complex to drive mitochondrial dysfunction.