Role of Recombinant S100A13 Expression in Regulating Mitochondrial Fission and Fusion in Lung Epithelial Cells

S100A13, a calcium-binding protein containing two EF-hand motifs, contributes to intracellular calcium homeostasis, a key determinant of mitochondrial quality control. We previously showed that S100A13 modulates mitochondrial membrane potential (ΔΨm) in patient-derived skin fibroblasts carrying S100A13 (p.I80Gfs*13 ) and S100A3 (p.R77C) mutations. However, its role in regulating mitochondrial dynamics remains unclear. Here, we investigated whether S100A13 regulates mitochondrial fusion–fission balance in human bronchial epithelial cells (BEAS-2B) using Myc-tagged wild-type or p.I80Gfs*13 S100A13 constructs. The S100A13 p.I80Gfs*13 mutant markedly attenuated bradykinin- and ionophore-induced intracellular calcium transients and reduced ΔΨm compared with wild-type S100A13 ( p < 0.05). These alterations were associated with severe mitochondrial ultrastructural abnormalities, disrupted cristae organization, and increased mitochondrial fragmentation ( p < 0.05). Interestingly, both wild-type and p.I80Gfs*13 mutant S100A13 increased expression of the mitochondrial fusion-associated proteins MFN1/2 and OPA1 while reducing expression of the fission mediator MFF. However, despite these apparently pro-fusion molecular changes, the S100A13 p.I80Gfs*13 mutant failed to maintain mitochondrial fusion competency, suggesting a functional uncoupling between fusion protein abundance and mitochondrial fusion competency. Collectively, these findings identify S100A13 as an important regulator of intracellular calcium-dependent mitochondrial dynamics and demonstrate that C-terminal truncation disrupts calcium-dependent regulation of mitochondrial fusion and cristae integrity in lung epithelial cells.