SS-31

What is SS-31 peptide?

SS-31 is a small, 4-amino acid, mitochondria-targeting peptide, found to have antioxidant and cell-protective effects [1]. Made up of alternating aromatic and basic amino acids, it contains a dimethyl tyrosine residue that neutralizes reactive oxygen species (ROS) and prevents lipid peroxidation [1].

Pharmacologically, SS-31 is water-soluble, stable, and resistant to enzymatic breakdown [1]. It can easily penetrate cell membranes due to its structure. It is distributed widely throughout the body, with the highest concentrations in the kidneys, and is completely excreted in urine [1]. Clinical studies show it is generally safe, with only mild side effects at the injection site, and no serious problems reported [1].

Once within cells, SS-31 rapidly accumulates in the inner mitochondrial membrane, up to 5,000 times more than in the surrounding cellular environment. Inside the mitochondria, it stabilizes cardiolipin, a critical phospholipid involved in the electron transport chain [1]. By doing so, SS-31 reduces electron leakage, preserves mitochondrial structure, and enhances ATP production [1].

Because cardiolipin damage has been implicated in various conditions such as neurodegeneration, heart failure, and mitochondrial myopathies, SS-31 has been studied as a novel therapeutic and promising candidate for conditions driven by mitochondrial dysfunction [2].

SS-31 benefits, mechanisms of action, and side effects

SS-31 attaches to cardiolipin, a phospholipid found within the inner layer of the mitochondria that helps maintain structure and stability [3]. In doing so, it protects cardiolipin and supports the electron transport chain [4]. This allows SS-31 to improve ATP production and counteract the impacts of oxidative stress [4]. SS-31 also activates specific antioxidant pathways, upregulating specific proteins that help protect against oxidative stress and ferroptosis cell damage [2].

Clinical and pre clinical studies have demonstrated its protective activities in cardiac, neurological, renal, and skeletal muscle tissues [5, 6, 7, 8, 9]. In models of spinal cord injuries, it also has neuroprotective activities [10].

Mitochondrial function and apoptosis

SS-31, through cardiolipin binding, preserves cristae architecture and supports efficient ATP production and electron transport [11]. As a strong antioxidant, it scavenges mitochondrial ROS to restore membrane potential and enhance the cell’s ATP generation [3]. Together, these mechanisms explain why SS-31 can maintain mitochondrial morphology, and prevent swelling and depolarization under stress conditions [12].  SS-31 upregulates SIRT1 expression, which suggests it may improve mitochondrial resilience and cellular metabolism through gene regulation [13].

Cardiolipin stabilization from SS-31 also prevents its peroxidation, reducing cytochrome C leakage and activation of apoptotic pathways [10]. SS-31 lowers caspase-3 activity, shifts specific pathways towards cell survival, and reduces DNA fragmentation to prevent apoptosis [14].

Heart health

SS-31 protects and restores heart health, particularly in conditions associated with heart failure, hypertension, atherosclerosis, and decreased blood flow [15]. By binding and stabilizing within mitochondrial membranes, SS-31 lowers oxidative stress and improves energy production [16]. In models of aging hearts, it restores healthy diastolic function and lowers oxidative damage without interfering with systolic function [16]. SS-31 repairs age-related changes in important heart proteins, improving muscle relaxation and resilience [17].

In models of cardiomyopathy and heart failure, SS-31 prevents apoptosis, limits scarring and thickening of cardiac muscle, and improves overall energy efficiency [5]. This remains even when blood pressure remains high [18]. It also strengthens aerobic metabolism, helping the heart meet high energy demands [19].

Within the blood vessels, SS-31 lowers inflammation, stabilizes atherosclerotic plaques, and enhances ATP production [20]. In ischemia-reperfusion, SS-31 reduces tissue damage and speeds recovery [21].

Antioxidant and anti-inflammatory properties

SS-31 can neutralize reactive oxygen species and provide protection for mitochondrial membranes [22]. By binding cardiolipin, SS-31 prevents cardiolipin peroxidation, which helps preserve mitochondrial integrity, limit cytochrome C leakage, and protect against mitochondrial dysfunction [23]. One study found SS-31 was able to prevent depletion of key antioxidant enzymes, including myeloperoxidase and superoxide dismutase, helping maintain redox balance [24]. By limiting oxidative damage, SS-31 can preserve mitochondrial energy output, limiting further ROS generation.

SS-31 also has anti-inflammatory impacts, with research finding it can lower levels of TNF-α, IL-1β, and IL-6 in lung tissue. These cytokines are key mediators of inflammatory and fibrotic signaling [22]. Because high ROS amplifies profibrotic pathways, reducing ROS indirectly lowers inflammation and fibrosis. Through its impacts on myeloperoxidase, SS-31 reduces neutrophil-driven tissue injury and inflammation [22].