Hazel H Szeto* Pages 1 - 16 ( 16 )
Mitochondria are the primary source of energy in most tissues and are particularly important for tissues with high energy demand such as skeletal muscle, heart, brain and retina. Mitochondrial dysfunction results in cellular energy deficiency, triggers the production of reactive oxygen species, and initiates various cell death and inflammatory pathways. This review describes a family of mitochondria-targeted tetrapeptides (SS peptides) that have been shown to improve mitochondrial bioenergetics, reduce mitochondrial oxidative stress, and prevent cell death and inflammation. There are a number of surprising features about these peptides. They share an aromatic-cationic motif with 3+ net charge. These peptides may be viewed as “cloaked” or “stealth” peptides as they can evade cellular membranes and readily penetrate all cells, even penetrating the blood-brain barrier. They have a unique and novel mechanism of action. Rather than target a single protein, these aromatic-cationic peptides target cardiolipin to induce structural change in the membrane and modify the spatial organization of multiple electron transport chain proteins to optimize electron transfer and ATP production. The actions of these aromatic-cationic peptides go beyond improving mitochondrial bioenergetics. In preclinical disease models, these peptides have been shown to repair damaged mitochondria and promote cellular repair and restore function. By mitigating cell injury, these peptides prevent inflammatory responses that can result in chronic inflammation and tissue remodeling. This review compiles all preclinical studies with SS-31, including muscle weakness, heart failure, kidney diseases, vision loss and neurodegenerative diseases. The breath of these preclinical studies confirms the fundamental importance of mitochondrial bioenergetics in age-related chronic diseases. Ongoing clinical trials with SS-31 (elamipretide) in rare inherited mitochondrial diseases and common age-related diseases are also summarized. This peptide technology platform represents a paradigm shift in targeting the fundamental cause of cellular energy failure for age-related degenerative diseases.
Aromatic-cationic peptides, mitochondria, cardiolipin, SS-31, elamipretide, reactive oxygen species, apoptosis, autophagy, inflammasome.
Innovative Mitochondrial Therapeutics New York, NY