Abstract
This study examines cardiolipin (CL) as a unique mitochondrial phospholipid that not only fulfills structural functions within the inner mitochondrial membrane but also acts as a programmable signaling hub. Current perspectives on CL biosynthesis, remodeling, and oxidative modifications are analyzed, alongside its role in stabilizing cristae, respiratory supercomplexes, mitophagy, apoptosis, and innate immunity. Based on the concept of CL-dependent signaling platforms – specifically the catalytic peroxidase, receptor-like mitophagic, caspase-8/BID-activation, and emergent immune platforms – it is demonstrated how dysregulation of CL metabolism is linked to the pathogenesis of Barth syndrome, myocardial ischemia-reperfusion injury, neurodegenerative and metabolic diseases, and glioblastoma. Particular emphasis is placed on therapeutic strategies: CL stabilization using elamipretide and second-generation peptides, TAZ gene therapy, inhibition of ALCAT1 and ABHD18, and control of substrate flux. The proposition is substantiated that targeting CL represents a promising yet conditionally effective approach: it confers the greatest benefit when residual mitochondrial architecture is preserved and during relatively early disease stages, whereas in fibrosis-dominant or advanced phenotypes, improvements in mitochondrial respiration may fail to translate into organ-level functional outcomes. The limitations of existing evidence are critically evaluated, specifically the reliance on reconstituted systems and animal models, conflicting data regarding the strict requirement of CL peroxidation for cytochrome c release, and divergent outcomes across elamipretide clinical trials. Emphasis is placed on the necessity of patient stratification based on genotype, disease stage, the functional state of respiratory supercomplexes, and CL lipidomic signatures. It is concluded that CL serves as a central hub of mitochondrial signaling and a promising, yet biologically constrained, therapeutic target, with future progress contingent upon integrating mechanistic, lipidomic, and clinical approaches.