Stem Cell Factor HGF Reverses Kidney Aging by Fixing Mitochondrial Copper Overload
Human umbilical cord stem cells release HGF to redirect STAT3 into mitochondria, clearing copper buildup and restoring respiratory function after acute kidney injury.
Summary
After acute kidney injury (AKI), copper accumulates in kidney mitochondria and drives cellular senescence. Researchers found that human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) secrete hepatocyte growth factor (HGF), which activates the cMet receptor on renal tubular cells. This triggers STAT3 phosphorylation at serine-727 and its translocation into mitochondria (mitoSTAT3). Once inside mitochondria, STAT3pSer727 physically binds COX17—a copper chaperone critical for respiratory complex IV—enhancing copper export and restoring energy production. Blocking any step in this pathway (HGF, cMet, mitoSTAT3, or COX17) worsened copper accumulation, impaired complex IV activity, and increased senescence markers, while restoring the pathway reduced them. The findings reveal a targetable molecular axis linking stem cell therapy to mitochondrial copper homeostasis and kidney aging.
Detailed Summary
Acute kidney injury (AKI) frequently progresses to chronic kidney disease, partly because injured renal tubular epithelial cells (RTECs) enter a senescent state driven by mitochondrial dysfunction. Copper overload in mitochondria is increasingly recognized as a driver of this dysfunction, yet the molecular mechanisms connecting stem cell therapy to mitochondrial copper handling were poorly understood.
This study used a mouse model of unilateral renal ischemia-reperfusion injury (uIRI) treated with renal subcapsular transplantation of hUC-MSCs embedded in collagen. Over 14 days, hUC-MSC treatment significantly improved serum creatinine and blood urea nitrogen, reduced fibrosis, and decreased canonical senescence markers including SA-β-galactosidase activity, p53, p21, and p16. Critically, levels of STAT3 phosphorylated at serine-727 (STAT3pSer727) and of the mitochondrial copper chaperone COX17 were both elevated by hUC-MSC treatment.
RNA sequencing of renal tissue identified copper homeostasis and respiratory chain complex IV as the top pathways enriched in MSC-treated animals. When HGF was knocked down in hUC-MSCs via lentiviral shRNA, all protective effects were reversed: STAT3pSer727 fell, COX17 decreased, mitochondrial copper accumulated, and the complex IV subunit mt-Co1 was reduced. Pharmacological inhibition of the HGF receptor cMet (SGX-523) replicated these effects in vivo, confirming that HGF signals through cMet to drive the mitochondrial STAT3 axis.
Mechanistic studies combined co-immunoprecipitation, molecular docking (ZDOCK 3.0.2), and all-atom molecular dynamics simulation (AMBER 20) to demonstrate that STAT3pSer727 forms a tight, stable complex with COX17. The phosphorylated form showed markedly lower binding energy, fewer structural fluctuations (RMSF/RMSD), and more stable hydrogen bonds compared to non-phosphorylated STAT3, indicating that serine-727 phosphorylation is specifically required for productive COX17 interaction. In hypoxia-reoxygenation models of primary mouse RTECs, blocking HGF or cMet with neutralizing antibodies reduced STAT3 mitochondrial translocation; pharmacological inhibition of mitoSTAT3 with mtcur-1 then decreased COX17 and mt-Co1. COX17 knockdown alone was sufficient to impair complex IV activity, increase mitochondrial and intracellular copper, elevate ROS, collapse mitochondrial membrane potential, open the mitochondrial permeability transition pore, reduce ATP production, and accelerate RTEC senescence.
Together, the data establish a linear paracrine axis: hUC-MSC-derived HGF → cMet → STAT3pSer727 → mitochondrial translocation → COX17 interaction → complex IV integrity → copper efflux and ATP synthesis → reduced RTEC senescence. This work identifies mitoSTAT3 and COX17 as druggable nodes linking MSC therapy to mitochondrial copper metabolism and post-AKI kidney aging, with potential implications for therapeutic strategies targeting cuproptosis-adjacent pathways in kidney disease.
Key Findings
- hUC-MSC transplantation improved renal function and reduced senescence markers p53, p21, p16, and SA-β-gal in AKI mice.
- RNA sequencing linked MSC benefit to copper homeostasis and mitochondrial respiratory complex IV pathways.
- HGF from MSCs drives STAT3 serine-727 phosphorylation and mitochondrial translocation via the cMet receptor.
- Phosphorylated mitoSTAT3 physically binds COX17, sustaining complex IV activity and mitochondrial copper export.
- COX17 knockdown alone caused copper accumulation, ROS elevation, ATP loss, and accelerated RTEC senescence.
Methodology
Mouse unilateral ischemia-reperfusion injury was treated with renal subcapsular hUC-MSC transplantation over 14 days; mechanisms were dissected using RNA sequencing, co-immunoprecipitation, ZDOCK molecular docking, AMBER molecular dynamics simulation, lentiviral knockdown, pharmacological inhibitors (SGX-523, mtcur-1), and primary RTEC hypoxia-reoxygenation models. Outcomes included renal function biomarkers, senescence staining, copper quantification, complex IV activity assays, mitochondrial membrane potential, ROS, and ATP levels.
Study Limitations
The study used only a unilateral IRI model in male mice, limiting generalizability to other AKI etiologies and both sexes. All in vitro work used mouse primary cells under hypoxia-reoxygenation, which incompletely recapitulates in vivo complexity. The direct therapeutic window and long-term safety of targeting mitoSTAT3 or COX17 in humans remain untested.
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