Objectives: Mitochondrial open-reading frame of the 12S ribosomal RNA type-c (MOTS-c) has anti-inflammatory and metabolic benefits. Mesenchymal stem/stromal cells (MSCs) offer treatment potential viadirect cellular interactions and paracrine effects, including extracellular vehicles (EVs). However, MSC and EVpotency in subjects with obesity is blunted, partly due to mitochondrial impairment. We hypothesized that a fallof MOTS-c expression in adipose tissue-derived (AT)-MSC from obese patients contributes to their dysfunctionin renovascular hypertensive (RVH) mice. Methods: AT-MSCs were isolated from subcutaneous fat of obese and age-matched lean subjects duringbariatric or kidney-donation surgeries, respectively. EVs were obtained from AT-MSC preconditioned with 10μMMOTS-c or vehicle for 48h. Two weeks after RVH intra-aortic AT-MSC or EVs were delivered in mice. Twoweeks later cardiac function was assessed in-vivo by MRI, and hearts studied ex-vivo . . Results: MOTS-c expression was markedly decreased in Obese-MSCs, associated with impairedmitochondrial function. Co-incubation restored MOTS-c levels. RVH-induced cardiac hypertrophy andmyocardial damage was attenuated by lean but not obese-MSCs or obese-EVs. MOTS-c preconditioningpartially restored obese-AT-MSCs functions, preventing blood pressure elevation, reducing hypertrophy, andimproving myocardial vascularization and redox status. Conclusion: Downregulation of MOTS-c in obese-MSCs in part impairs the reparative capacity of obesity-derived AT-MSCs. MOTS-c replenishment may enhance endogenous repair and autologous cell-basedtherapies in obesity.