Mitochondria, often described as the “powerhouse of the cell”, are responsible for approximately 90% of energy production in human cells.1 These “powerhouses” are found in all human cells other than red blood cells.2 Mitochondria produce energy through the conversion of food into adenosine triphosphate, or ATP. 2 This happens through a series of reactions, controlled by the electron transport chain, within the inner folds of the mitochondria.2 In normal mitochondria, the inner mitochondrial membrane is highly folded, creating curves, called cristae.3 The cristae house the electron transport chain, which is composed of five protein complexes responsible for mitochondrial ATP production.3 Cardiolipin, a phospholipid found only in the inner mitochondrial membrane, is responsible for establishing the cristae architecture and optimizing the function of the electron transport chain for ATP generation.4
Dysfunctional mitochondria produce less ATP and increased unhealthy levels of reactive oxygen species, or ROS, which leads to oxidative stress.2 Although low levels of ROS are normal and important for the cell, high levels of ROS can damage cardiolipin, thereby disrupting the structure of the inner mitochondrial membrane and triggering a cycle of increasing ROS generation that can lead to the inflammation, fibrosis, senescence and cell death implicated in many human diseases.5
Mitochondrial dysfunction characterizes numerous inherited rare diseases – collectively known as primary mitochondrial diseases – that arise from over 250 different genetic mutations.6 These include primary mitochondrial myopathy, Barth syndrome, and Leber’s hereditary optic neuropathy.7-8 Mitochondrial dysfunction is also involved in a wide range of common age-related diseases, such as dry age related macular degeneration.9-10
As the body’s main source of energy production, mitochondria are critical for normal organ function, particularly with respect to high energy demanding organ systems such as skeletal muscle, eye, brain, heart and kidney.10-12 Patients with mitochondrial disease often experience functional deficit in three or more of these organ systems.11-12
Healthy & Unhealthy
Our lead investigational product candidate, elamipretide, is a peptide compound that readily penetrates cell membranes, and targets the inner mitochondrial membrane where it binds reversibly to cardiolipin.13 In preclinical or clinical studies, we have observed that elamipretide increases mitochondrial respiration, improves the electron transport chain function and ATP production and reduces formation of pathogenic ROS levels.13-19 This elamipretide-cardiolipin association has been shown to normalize the structure of the inner mitochondrial membrane, thereby improving mitochondrial function.13 Functional benefit is achieved through improvement of ATP production and interruption and potential reversal of damaging oxidative stress.13 We are investigating elamipretide in late stage clinical studies in three primary mitochondrial diseases—primary mitochondrial myopathy, Barth syndrome and Leber’s hereditary optic neuropathy – as well as an earlier stage clinical study in dry age-related macular degeneration.