SS-31

Elamipretide: a mitochondria-targeting drug for Barth syndrome.

2026 · Preclinical

Elamipretide (SS-31) promotes recovery by preserving mitochondrial bioenergetics and neural remodeling after spinal cord injury.

2026 · Neurochemistry international · Preclinical

Spinal cord injury (SCI) induces secondary damage characterized by mitochondrial dysfunction, oxidative stress, and apoptosis, which collectively impede neurological recovery. Elamipretide (SS-31) is a mitochondria-targeting peptide with potential neuroprotective effects. Here, we investigated whether SS-31 improves functional outcomes after contusive SCI and explored associated mechanisms. In a mouse thoracic contusion model, SS-31 treatment significantly enhanced locomotor recovery and gait performance. Histological analyses showed reduced lesion pathology and increased neuronal preservation in the injured spinal cord. Early after injury, SS-31 attenuated apoptosis signaling, evidenced by reduced cleaved caspase-3 and Bax and increased Bcl-2. At the chronic stage, SS-31 was associated with diminished astrogliosis and enhanced markers of axonal and synaptic remodeling. In oxidatively stressed PC12 cells, SS-31 preserved mitochondrial membrane potential, reduced ROS accumulation, and supported oxidative phosphorylation-related protein integrity. Collectively, these findings suggest that SS-31 promotes recovery after SCI, potentially by mitigating early apoptotic injury and supporting mitochondrial homeostasis and neural remodeling.

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

2026 · Journal of radiation research · Preclinical

Exposure to ionizing radiation, such as from radiation therapy or accidental radiation exposure can have adverse effects on the heart. While radiation injury in the heart may include cardiomyocyte senescence, there are no available strategies to prevent this phenomenon. This study evaluated the effects of the mitochondrial-targeted peptide SS-31 (elamipretide) on radiation-induced cell senescence in cardiomyoblast H9C2 cells and human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). Exposure to γ-radiation at doses of 2, 5, and 10 Gy inhibited H9C2 cell proliferation in a dose-dependent manner, and induced senescence-associated beta-galactosidase (SA-β-gal) staining, a gold standard of cell senescence. Treatment with SS-31 (1 μM) for 7 days reduced SA-β-gal positive staining from 67% to 38% in H9C2 cells under 10 Gy radiation. SS-31 also prevented increases in the expression of p16 and p21, two well-accepted senescence markers, in irradiated H9C2 cells and hiPSC-CMs. SS-31 decreased the canonical senescence-associated secretory phenotype markers TNF-α, IL-6, and IL-1β. SS-31 also reversed the BAX/bcl-2 ratio, a marker of mitochondrial-related apoptosis. Moreover, SS-31 mitigated mitochondrial production of reactive oxygen species. Interestingly, we found that a dose of 10 Gy increased mitochondrial respiration, and SS-31 reversed this elevation. This study suggests that SS-31 is a promising compound that may prevent radiation-induced cardiomyocyte senescence.

Elamipretide (SS-31) and Nicotinamide Mononucleotide (NMN) Combination Therapy Targets TREM2 to Mitigate Post-ischemic Brain Injury in Mice.

2026 · Neurochemical research · Preclinical

Ischemic stroke is a severe cerebrovascular disorder characterized by a cascade of pathological processes, including neuroinflammation and apoptosis. These processes lead to high mortality rates and long-term disabilities, imposing substantial socioeconomic burdens. Although reperfusion therapies have improved patient outcomes, many remain ineligible due to narrow therapeutic windows or clinical contraindications. Consequently, developing novel neuroprotective strategies is of significant clinical importance. Elamipretide (SS-31) and nicotinamide mononucleotide (NMN) are well-documented neuroprotective agents operating through distinct mechanisms; however, their combined efficacy and underlying mechanisms in ischemic stroke remain elusive. This study investigated the neuroprotective efficacy of SS-31 and NMN, alone or in combination, in a mouse model of ischemic stroke, with a specific focus on their modulation of triggering receptor expressed on myeloid cells 2 (TREM2)-mediated neuroinflammatory and apoptotic pathways. A middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in male mice, followed by treatment with SS-31, NMN, or their combination. Therapeutic outcomes were evaluated using neurobehavioral scoring, histopathological staining, transcriptomic sequencing, and protein expression analyses. TREM2 overexpression experiments and specific pharmacological inhibition of the NF-κB pathway were conducted to elucidate the specific molecular mechanisms. Co-administration of SS-31 and NMN significantly attenuated post-ischemic brain damage and ameliorated neurological deficits (P < 0.0001), demonstrating effects markedly superior to either monotherapy. Transcriptomic profiling revealed that the combination therapy specifically modulated innate immune and apoptotic pathways, concomitant with a significant downregulation of TREM2. Mechanistically, the combination therapy effectively inhibited NF-κB (p65) activation, thereby downregulating TREM2 expression. This suppression attenuated microglial activation, reduced the expression of canonical pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6), and rebalanced the Bcl-2/Bax apoptotic axis. Overexpression of TREM2 entirely reversed these neuroprotective benefits. Combination therapy with SS-31 and NMN provides robust neuroprotection against ischemic stroke by suppressing the NF-κB/TREM2 signaling axis, thereby combinatorially modulating post-stroke neuroinflammation and apoptosis. These findings highlight a novel, multi-targeted strategy for precision stroke interventions.

Genotype-specific effects of elamipretide in patients with primary mitochondrial myopathy: a post hoc analysis of the MMPOWER-3 trial.

2024 · Orphanet journal of rare diseases · Human evidence

Background As previously published, the MMPOWER-3 clinical trial did not demonstrate a significant benefit of elamipretide treatment in a genotypically diverse population of adults with primary mitochondrial myopathy (PMM). However, the prespecified subgroup of subjects with disease-causing nuclear DNA (nDNA) pathogenic variants receiving elamipretide experienced an improvement in the six-minute walk test (6MWT), while the cohort of subjects with mitochondrial DNA (mtDNA) pathogenic variants showed no difference versus placebo. These published findings prompted additional genotype-specific post hoc analyses of the MMPOWER-3 trial. Here, we present these analyses to further investigate the findings and to seek trends and commonalities among those subjects who responded to treatment, to build a more precise Phase 3 trial design for further investigation in likely responders. Results Subjects with mtDNA pathogenic variants or single large-scale mtDNA deletions represented 74% of the MMPOWER-3 population, with 70% in the mtDNA cohort having either single large-scale mtDNA deletions or MT-TL1 pathogenic variants. Most subjects in the nDNA cohort had pathogenic variants in genes required for mtDNA maintenance (mtDNA replisome), the majority of which were in POLG and TWNK. The mtDNA replisome post-hoc cohort displayed an improvement on the 6MWT, trending towards significant, in the elamipretide group when compared with placebo (25.2 ± 8.7 m versus 2.0 ± 8.6 m for placebo group; p = 0.06). The 6MWT results at week 24 in subjects with replisome variants showed a significant change in the elamipretide group subjects who had chronic progressive external ophthalmoplegia (CPEO) (37.3 ± 9.5 m versus - 8.0 ± 10.7 m for the placebo group; p = 0.0024). Pharmacokinetic (exposure-response) analyses in the nDNA cohort showed a weak positive correlation between plasma elamipretide concentration and 6MWT improvement. Conclusions Post hoc analyses indicated that elamipretide had a beneficial effect in PMM patients with mtDNA replisome disorders, underscoring the importance of considering specific genetic subtypes in PMM clinical trials. These data serve as the foundation for a follow-up Phase 3 clinical trial (NuPOWER) which has been designed as described in this paper to determine the efficacy of elamipretide in patients with mtDNA maintenance-related disorders. Classification of evidence Class I CLINICALTRIALS. Gov identifier NCT03323749.