Molecular Mechanisms by Which Mitochondrial Homeostasis Imbalance Regulates Ferroptosis and Inflammatory Responses

Mitochondria coordinate energy conversion, redox buffering, iron utilization, lipid metabolism, organelle dynamics, and innate immune sensing. Disruption of these processes alters the threshold for ferroptosis, an iron-dependent form of regulated cell death driven by phospholipid peroxidation, and also supplies inflammatory signals that reshape tissue microenvironments. Work published during the past five years has moved the field beyond a simple view in which mitochondria act only as sources of reactive oxygen species. Mitochondrial iron handling, tricarboxylic acid cycle activity, electron transport, ubiquinone metabolism, mitochondrial glutathione, dihydroorotate dehydrogenase, outer-membrane permeabilization, mitophagy, and organelle contact sites each contribute to ferroptotic susceptibility in a context-dependent manner. Mitochondrial damage further releases mitochondrial DNA, cardiolipin-related danger signals, oxidized lipids, and metabolic intermediates that engage cGAS-STING, inflammasome, NF-kappaB, and macrophage polarization pathways. This review summarizes recent progress in mitochondrial homeostasis, ferroptosis regulation, and inflammatory signaling, with emphasis on molecular coupling among mitochondrial iron imbalance, lipid peroxidation, redox stress, quality control failure, and inflammation-driven feedback. A more integrated interpretation of these pathways may support biomarker development and therapeutic strategies for cancer, ischemic injury, neurodegeneration, infection-related organ damage, and chronic inflammatory diseases.