First‐in‐class cardiolipin‐protective compound as a therapeutic agent to restore mitochondrial bioenergetics

<jats:sec><jats:label /><jats:p>A decline in energy is common in aging, and the restoration of mitochondrial bioenergetics may offer a common approach for the treatment of numerous age‐associated diseases. Cardiolipin is a unique phospholipid that is exclusively expressed on the inner mitochondrial membrane where it plays an important structural role in cristae formation and the organization of the respiratory complexes into supercomplexes for optimal oxidative phosphorylation. The interaction between cardiolipin and cytochrome <jats:italic>c</jats:italic> determines whether cytochrome <jats:italic>c</jats:italic> acts as an electron carrier or peroxidase. Cardiolipin peroxidation and depletion have been reported in a variety of pathological conditions associated with energy deficiency, and cardiolipin has been identified as a target for drug development. This review focuses on the discovery and development of the first cardiolipin‐protective compound as a therapeutic agent. <jats:styled-content style="fixed-case">SS</jats:styled-content>‐31 is a member of the <jats:styled-content style="fixed-case">S</jats:styled-content>zeto‐<jats:styled-content style="fixed-case">S</jats:styled-content>chiller (<jats:styled-content style="fixed-case">SS</jats:styled-content>) peptides known to selectively target the inner mitochondrial membrane. <jats:styled-content style="fixed-case">SS</jats:styled-content>‐31 binds selectively to cardiolipin via electrostatic and hydrophobic interactions. By interacting with cardiolipin, <jats:styled-content style="fixed-case">SS</jats:styled-content>‐31 prevents cardiolipin from converting cytochrome <jats:italic>c</jats:italic> into a peroxidase while protecting its electron carrying function. As a result, <jats:styled-content style="fixed-case">SS</jats:styled-content>‐31 protects the structure of mitochondrial cristae and promotes oxidative phosphorylation. <jats:styled-content style="fixed-case">SS</jats:styled-content>‐31 represents a new class of compounds that can recharge the cellular powerhouse and restore bioenergetics. Extensive animal studies have shown that targeting such a fundamental mechanism can benefit highly complex diseases that share a common pathogenesis of bioenergetics failure. This review summarizes the mechanisms of action and therapeutic potential of <jats:styled-content style="fixed-case">SS</jats:styled-content>‐31 and provides an update of its clinical development programme.</jats:p></jats:sec><jats:sec><jats:title>Linked Articles</jats:title><jats:p>This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="http://dx.doi.org/10.1111/bph.2014.171.issue-8">http://dx.doi.org/10.1111/bph.2014.171.issue‐8</jats:ext-link></jats:p></jats:sec>