<p>Sepsis-associated acute kidney injury (S-AKI) is a frequent and severe complication of sepsis in which metabolic dysfunction and inflammatory activation develop in parallel and reinforce each other. Although mitochondrial dysfunction is widely recognized in S-AKI, the structural mechanisms linking mitochondrial bioenergetic failure to innate immune signaling remain incompletely understood. Emerging evidence suggests that mitochondrial lipid remodeling—particularly alterations in cardiolipin (CL)—may represent a structural interface connecting these processes. As a signature phospholipid of the inner mitochondrial membrane, cardiolipin supports cristae architecture, stabilizes respiratory chain supercomplexes, and maintains efficient oxidative phosphorylation. In renal tubular epithelial cells, which depend heavily on mitochondrial oxidative metabolism, disruption of cardiolipin homeostasis may have particularly profound consequences. Under septic stress, oxidative injury and dysregulated lipid remodeling alter cardiolipin composition and distribution, contributing to respiratory chain instability, impaired ATP production, and increased reactive oxygen species generation. In parallel, cardiolipin oxidation or externalization can transform mitochondrial membranes into signaling platforms that promote inflammasome activation and mitochondrial danger-associated molecular patterns (mtDAMPs) release. In this review, we propose a cardiolipin-centered framework that integrates mitochondrial bioenergetic failure with inflammatory amplification in S-AKI. By positioning mitochondrial lipid remodeling at the intersection of metabolism and innate immunity, this framework highlights mitochondrial lipid homeostasis as a potential mechanistic node and therapeutic entry point in septic kidney injury.</p>