Mitochondrial-targeted SS-31 peptide attenuates radiation-induced cardiomyocyte senescence

SS-31 reduced radiation-induced senescence in cultured heart muscle cells, cutting SA-β-gal positive cells from 67% to 38% after 10 Gy and blocking senescence and inflammation markers. The study used rat H9C2 cardiomyoblasts and human stem-cell-derived cardiomyocytes and suggests mitochondrial ROS and respiration are involved.

Journal article — In vitro experimental cell study. Population: Rat H9C2 cardiomyoblasts and human induced pluripotent stem cell-derived cardiomyocytes exposed to γ-radiation. Follow-up: 7 days. Interventions: SS-31 (elamipretide) 1 μM.

In H9C2 cells, radiation inhibited proliferation dose-dependently and induced SA-β-gal staining. SS-31 at 1 μM for 7 days reduced SA-β-gal positivity from 67% to 38% in cells exposed to 10 Gy. SS-31 prevented increases in p16 and p21 in H9C2 cells and hiPSC-CMs, decreased TNF-α, IL-6, and IL-1β, reversed the BAX/bcl-2 ratio, mitigated mitochondrial ROS, and reversed the 10 Gy-induced increase in mitochondrial respiration.

For researchers studying SS-31, this paper provides in vitro evidence that SS-31 can oppose radiation-induced cardiomyocyte senescence, with effects on SA-β-gal, p16/p21, SASP markers, BAX/bcl-2, and mitochondrial ROS/respiration. It does not establish that SS-31 prevents radiation cardiotoxicity in animals or humans, nor does it test dosing beyond 1 μM for 7 days.

Key findings

• γ-radiation at 2, 5, and 10 Gy inhibited H9C2 cell proliferation in a dose-dependent manner.
• SS-31 (1 μM) for 7 days reduced SA-β-gal positive staining from 67% to 38% in H9C2 cells exposed to 10 Gy.
• SS-31 prevented radiation-induced increases in p16 and p21 expression in irradiated H9C2 cells and hiPSC-CMs.
• SS-31 decreased the senescence-associated secretory phenotype markers TNF-α, IL-6, and IL-1β.
• SS-31 reversed the BAX/bcl-2 ratio and mitigated mitochondrial reactive oxygen species production.
• 10 Gy increased mitochondrial respiration, and SS-31 reversed this elevation.

Limitations

• In vitro cell models only, with no animal or human confirmation.
• Single SS-31 concentration (1 μM) and 7-day exposure tested.
• Short-term assessment does not address long-term senescence or functional cardiac outcomes.
• Findings point to mitochondrial involvement but do not establish the full mechanism.

The record

• Journal: Journal of radiation research 67(4): 525-537
• Published: 2026-07-15
• PMID: 42456009 — DOI: 10.1093/jrr/rrag048
• MeSH terms: Cell Line, Mitochondria, Myocytes, Cardiac, Animals, Humans, Rats, Reactive Oxygen Species, Oligopeptides, Dose-Response Relationship, Radiation, Cell Proliferation, Cellular Senescence
• Funding: NIGMS NIH HHS; NIGMS; NIGMS NIH HHS; NIGMS NIH HHS; NIGMS NIH HHS; NIGMS; NIGMS; NIGMS
• Author countries: USA

Peptide profiles: SS-31.

All indexed evidence: SS-31 trials & papers.

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