It has been proposed that a loss of bioenergetic capacity of cells contributes to the progressive loss of biological function with age. Aging is associated with loss of mitochondrial cristae membranes and inhibition of ATP production. Despite the many approaches being pursued for improving mitochondrial function, none of them directly targets the electron transport chain to improve ATP production. Recent studies have brought attention to cardiolipin as a unique target for promoting mitochondrial efficiency. Cardiolipin is important for cristae curvatures and is necessary for optimal activity of the respiratory complexes and the assembly of supercomplexes. Here we describe the discovery of a class of cell-penetrating aromatic-cationic tetrapeptides that selectively target cardiolipin and increase coupling efficiency while reducing reactive oxygen species production. These compounds can rejuvenate mitochondrial bioenergetics, remodel mitochondrial cristae structure, repair cellular structure, and restore organ function during aging.