Organelle contact sites as intracellular communication hubs linking metabolic stress to inflammatory disease

Abstract Membrane contact sites (MCSs) are specialized, non-fusogenic interfaces that allow organelles to exchange ions, lipids, metabolites and stress signals. These contacts support adaptation to nutrient, proteotoxic and inflammatory stress. However, persistent or misregulated organelle communication can redirect metabolic stress toward chronic inflammatory injury. Here, we review how pathological remodeling of MCSs connects endoplasmic reticulum (ER) stress, mitochondrial dysfunction, lysosomal impairment, lipid toxicity and innate immune activation in disease. We focus on three interconnected signaling axes. First, ER–mitochondria contacts coordinate Ca 2+ transfer, redox signaling, mitochondrial quality control and danger-signal release. Second, mitochondria–lysosome contacts regulate nutrient sensing, mitochondrial fission and quality-control decisions beyond classical mitophagy. Third, lipid-centered contacts among the ER, lipid droplets and mitochondria shape whether lipid excess is buffered, oxidized or progresses to lipotoxic injury or ferroptotic stress. We propose that MCS remodeling should be viewed as an intracellular stress-distribution network rather than as isolated organelle-pair dysfunction. This network framework helps explain shared mechanisms across kidney, cardiometabolic, hepatic, neurodegenerative and cancer contexts. We also discuss methodological challenges in distinguishing organelle proximity from functional exchange, and outline therapeutic strategies aimed at restoring contact-site timing, composition and signal transfer. By placing organelle communication at the center of metabolic inflammation, this review highlights MCSs as dynamic disease modifiers and potential targets for normalizing pathological stress signaling.