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

“Mitochondrial-derived peptide MOTS-c activates metabolic signaling but blunts reparative function in human mesenchymal stromal cells. Xing L(1)(2), Lu B(1)(3), Zhu X(1), Al Saeedi M(1), Lerman A(4), Eirin A(1), Cohen P(5), Lerman LO(6). Author information: (1)Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA. (2)Department of Urology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu Province, China. (3)Department of Cardiology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China. (4)Department of Cardiology, Mayo Clinic, Rochester, MN, USA. (5)USC Leonard Davis School of Gerontology, Los Angeles, CA, USA. (6)Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA. lerman.lilach@mayo.edu. 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. © 2026. The Author(s). Conflict of interest statement: Declarations. Ethics approval and consent to participate: Title of the approved human study: “Obesity-induced mesenchymal stem cell senescence”. Name of the approving ethics committee: Mayo Clinic Institutional Review Board. Ethics approval reference number: 18-005076. Date approved: August 17, 2018. Consent for publication: Not applicable. Competing interests: Dr. Lerman is an advisor to CureSpec, LiveKidney.bio, and Cellergy. The authors declare no conflict.”