Association between FNDC5 Deficiency and Compromised Mitochondrial Integrity and Biogenesis in Kidney Disease

Background: Mitochondrial dysfunction is a hallmark of acute and chronic kidney diseases.This study investigates the expression landscape and potential association of FNDC5 with renal injury.Methods: We integrated human scRNA-seq, mouse spatial transcriptomics (ischemia-reperfusion injury model), in vitro high-glucose (HG) models in proximal tubule cells and podocytes, and a constitutive Fndc5 knockout mouse model.Candidate transcription factor occupancy at the FNDC5 promoter was examined by ChIP-qPCR, and associations were assessed in a non-insulin-dependent diabetes mellitus mouse model.Results: scRNA-seq localized FNDC5 to specific tubules, showing downregulation in diabetic nephropathy.Spatial transcriptomics confirmed a distinct loss of cortical Fndc5 following ischemia-reperfusion injury.In vitro, HG treatment suppressed FNDC5, reduced cell viability, and triggered mitochondrial fragmentation, evidenced by increased DRP1 phosphorylation and downregulated MFN1/OPA1.ZEB1 and CREB1 were identified as candidate transcription factors showing occupancy at the FNDC5 promoter.Genetic deletion of Fndc5 reproduced this fission-permissive shift and reduced PGC1α expression under basal, non-diabetic conditions, providing loss-of-function evidence that Fndc5 deficiency is sufficient to reproduce this phenotype, independent of any additional metabolic stressor.In vivo, diabetic mice exhibited diminished FNDC5 levels, which correlated with an oxidative stress-associated marker (4-HNE) and reduced expression of the biogenesis-associated marker PGC1α.Conclusion: FNDC5 downregulation is a conserved feature of renal injury associated with mitochondrial fission, and genetic loss-of-function data indicates that Fndc5 deficiency is sufficient to reproduce selected features of this fission-permissive mitochondrial phenotype; whether FNDC5 acts through a defined downstream pathway remains to be established.