Improved Mitochondrial Function with SS-31

Primary mitochondrial diseases (PMDs) are prevalent hereditary conditions globally. These diseases arise from dysfunction in the mitochondria's energy-producing mechanism. Symptoms vary across different forms of the disease, with organ systems that have high energy demands, such as the nervous system, heart, and kidney, being the most affected. Mitochondrial disorders commonly exhibit muscle involvement, exercise intolerance, and symptoms like fatigue and seizures.

PMDs and mitochondrial diseases are predominantly characterized by disruptions in ATP production. ATP serves as the cell's energy currency and is essential for almost every cellular function. The medical community has long aimed to stabilize ATP production in the presence of mitochondrial disease.

Initial evidence of SS-31's ability to restore energy production in PMDs emerged from animal studies. Rats suffering from kidney ischemia-perfusion injury, a non-genetic cause of mitochondrial disease, were administered SS-31. The peptide protected kidney structure, expedited ATP production recovery, and reduced cell death and necrosis within the kidney. Further studies on mice demonstrated that SS-31 interacted with cardiolipin in the inner mitochondrial membrane, indicating its effectiveness in alleviating mitochondrial disease symptoms regardless of its cause. It also displayed potential in improving age-related mitochondrial dysfunction. Consequently, SS-31 obtained orphan drug status from the FDA, leading the way for clinical trials.

Currently, SS-31 is undergoing testing in various human diseases using different trial models.

Ischemia and the Potential of SS-31

One of the most promising research fields for secondary applications of SS-31 is in the treatment of heart failure. It is well-known that heart failure negatively impacts mitochondrial function, resulting in a cycle where heart failure worsens. Studies conducted on human heart tissue treated with SS-31 demonstrated notable improvements in mitochondrial oxygen flux and the activity of specific ATP-producing components. Notably, this study excluded cardiolipin restructuring, implying the existence of other mechanisms by which SS-31 affects mitochondrial function. This finding has been replicated in several research projects, strengthening the possibility that SS-31 is not solely limited to restoring ATP production through cardiolipin interaction. Researchers are actively exploring SS-31's potential to modulate the production of reactive oxygen species, enhance mitochondrial function, and address acute and chronic conditions related to heart failure.

In canine studies, chronic SS-31 treatment demonstrated improved left ventricular function in advanced heart failure cases. The study correlated measures of mitochondrial respiration and maximum ATP synthesis with overall enhancements in left ventricular function, suggesting that SS-31 could serve as a long-term treatment option to improve energy dynamics and reduce cardiac remodeling. Trials investigating the use of SS-31 in cases of ST-segment elevation myocardial infarction (heart attack) indicated a significant reduction in HtrA2 levels, a marker of cardiomyocyte apoptosis. This suggests that SS-31 may effectively minimize injury extent and preserve cardiac tissue in acute heart attack scenarios.

Mitochondrial-targeted therapy plays a pivotal role in heart failure treatment:

Diabetes and Mitochondrial Dysfunction

Diabetes, typically associated with insulin secretion or function deficiencies, is a complex condition with diverse pathophysiologic manifestations. In recent years, there has been growing interest in the role of mitochondrial impairment in the development of diabetes, particularly type 2 diabetes. Treating mitochondrial dysfunction could potentially alleviate long-term consequences such as oxidative damage to small blood vessels. In a study involving humans administered SS-31, a noticeable decrease in reactive oxygen species production was observed. This suggests that SS-31 may contribute to reducing oxidative damage resulting from mitochondrial dysfunction, potentially slowing down or preventing the progression of microvascular disease in type 2 diabetes. Additionally, this study revealed elevated levels of SIRT1, which are associated with improved insulin sensitivity and reduced inflammation in type 2 diabetes.

Anti-Inflammatory Properties of SS-31

A consistent theme observed in the aforementioned sections is the anti-inflammatory effect of SS-31. The peptide has been found to regulate reactive oxygen species, mitigating the oxidative stress commonly associated with long-term illnesses such as diabetes and heart disease. Cell culture research indicates that SS-31 can reduce inflammation and oxidative stress by suppressing the expression of FIS1, an important mitochondrial protein involved in growth and division. Increased levels of FIS1 have been linked to dysfunctional mitochondrial division secondary to inflammation and dysfunction, observed in neurodegenerative diseases and various cancers.

Further research in mouse models has demonstrated that SS-31 can reduce levels of the inflammatory cytokine CD-36, suppress the expression of activated MnSOD, inhibit NADPH oxidase function, and impede NF-kappaB p65. These markers indicate reduced oxidative stress, suggesting decreased free radical production and improved inflammatory status within cells. NF-kappaB expression is particularly associated with cellular inflammation and is persistently active in conditions like rheumatoid arthritis and inflammatory bowel disease. SS-31 prevents inflammasome activation and preserves normal mitochondrial function.

Summary of SS-31

While initially investigated for its potential to regulate mitochondrial function in mitochondrial diseases, there is substantial evidence indicating that SS-31 can also modulate mitochondria-induced inflammation. Ongoing phase II trials and planned phase III trials are exploring the use of SS-31 in various disease states, employing different outcome measures. SS-31 might hold the key to comprehending mitochondrial dysfunction in diseases such as Alzheimer's, Parkinson's, heart disease, diabetes, and kidney disease, potentially leading to advanced treatment strategies.