Inflammation and Regeneration · Jun 22, 2026

Mitochondrial-derived peptide MOTS-c activates metabolic signaling but blunts reparative function in human mesenchymal stromal cells

By Xing L, Lu B, Zhu X et al.

BACKGROUND: Mesenchymal stromal cells (MSCs) possess therapeutic potential largely reliant on intact mitochondrial function to maintain reparative function. However, obesity compromises MSC metabolism and reparative capacity. MOTS-c, a mitochondria-derived peptide, is known to regulate cellular metabolism, but its role in human MSC biology remains unclear. We hypothesized that restoring MOTS-c signaling rescues the impaired functionality of adipose-derived MSCs from individuals with obesity. METHODS: MSCs isolated from abdominal fat of patients with obesity (BMI ≥ 30 kg/m²) and lean donors (BMI < 30 kg/m²) (n = 6/group) were assessed in vitro for changes in proliferation, senescence (p16, p21) TNF-α, and antioxidant gene expression following MOTS-c co-incubation. In vivo, the effects of MOTS-c pre-treatment on the reparative capacity of obese MSC were tested in stenotic mouse kidneys. RESULTS: Basal MOTS-c expression was lower in obese vs. lean MSCs. Nevertheless, although exogenous MOTS-c restored intracellular levels and activated AMPK signaling in obese MSCs, it reduced proliferation, increased expression of senescence-associated genes (p16, p21), and upregulated TNF-α. In vivo, in a murine model of renal artery stenosis, MOTS-c-pretreated MSCs failed to improve renal perfusion, fibrosis, or tubular injury, while pretreatment also blunted the reparative efficacy of lean MSCs. These findings reveal that restoration of mitochondrial metabolic signaling is insufficient to reverse obesity-induced MSC dysfunction and may paradoxically exacerbate senescence and inflammation. CONCLUSION: These results suggest a dissociation between metabolic activation and functional stemness, underscoring context-dependent effects of mitochondrial-derived peptides in MSC biology.

doi.org/10.1186/s41232-026-00431-7 Open access PubMed 42324588 Interventions