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

Treating human adipose-derived mesenchymal stromal cells with MOTS-c activated a metabolic signaling pathway but also made the cells less proliferative, more senescence-associated, and more inflammatory. In a mouse model of kidney injury, MOTS-c-pretreated MSCs did not improve repair and blunted the benefit of MSCs from lean donors. The authors conclude that restoring mitochondrial metabolic signaling is insufficient to reverse obesity-related MSC dysfunction.

Journal article — In vitro and in vivo mouse model. Population: Human abdominal-fat MSCs from patients with obesity (BMI ≥30 kg/m2) and lean donors, tested in stenotic mouse kidneys. Sample size: 6 per group (MSC donors). Interventions: MOTS-c co-incubation of MSCs in vitro; MOTS-c pre-treatment of MSCs in a mouse renal artery stenosis model.

In vitro, MSCs from 6 obese and 6 lean donors showed lower basal MOTS-c expression in obese MSCs than in lean MSCs. Exogenous MOTS-c restored intracellular levels and activated AMPK signaling in obese MSCs, but it reduced proliferation, increased p16 and p21 expression, and upregulated TNF-α. In a mouse renal artery stenosis model, MOTS-c-pretreated MSCs failed to improve renal perfusion, fibrosis, or tubular injury, and MOTS-c pretreatment also blunted the reparative efficacy of lean MSCs.

Researchers studying MOTS-c should note this paper as evidence that metabolic activation via AMPK does not necessarily preserve or improve MSC stemness or repair, and may worsen senescence and inflammation. The study does not establish any therapeutic benefit of MOTS-c in kidney repair or in obesity-related MSC dysfunction, and it provides no dose, timing, or mechanistic detail beyond AMPK activation. It also does not test MOTS-c directly in humans.

Key findings

• In MSCs from 6 obese and 6 lean donors, basal MOTS-c expression was lower in obese MSCs than in lean MSCs.
• Exogenous MOTS-c restored intracellular MOTS-c levels and activated AMPK signaling in obese MSCs.
• MOTS-c treatment of obese MSCs reduced proliferation and increased p16, p21, and TNF-α expression.
• In a mouse renal artery stenosis model, MOTS-c-pretreated MSCs failed to improve renal perfusion, fibrosis, or tubular injury.
• MOTS-c pretreatment also blunted the reparative efficacy of lean MSCs.

Limitations

• The abstract lists no study limitations.
• In vitro and mouse-model design limits direct translation to human therapy.
• Only 6 MSC donors per group were used.
• No clinical outcomes in patients with obesity were measured.

The record

• Journal: Inflammation and regeneration
• Published: 2026-06-22
• PMID: 42324588 — DOI: 10.1186/s41232-026-00431-7
• Author countries: China, USA

Peptide profiles: MOTS-c.

All indexed evidence: MOTS-c trials & papers.

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