Cardiolipin remodelling in mitochondrial therapeutics: translational evidence chains from elamipretide to emerging strategies

Mitochondrial therapeutics have repeatedly fallen short of disease modification, in part because inner-membrane architecture constrains both molecular access and the reversibility of bioenergetic failure. Cardiolipin (CL), the signature phospholipid of the inner mitochondrial membrane, provides a mechanistically cohesive axis that links membrane mechanics to cristae organisation, respiratory-chain supercomplex stability and redox vulnerability. This Review summarises how CL biosynthesis and remodelling shape tissue-specific lipid species and how pathological remodelling can amplify oxidative injury. The MLCL: CL ratio is discussed as a rare lipid biomarker with direct interpretability for diagnosis, stratification and target engagement. Clinical evidence for CL-targeting stabilisers is evaluated to delineate settings in which structural support yields functional benefit and those in which organ-level remodelling limits translation despite improved respiration. Emerging approaches that improve tissue distribution, modulate membrane phase behaviour or rebalance upstream lipid flux are considered alongside trial designs that couple target-proximal readouts to patient-relevant endpoints, paving the way for precision medicine in mitochondrial lipodystrophies.