The Role of Metal Ions in Mitochondria: From Energy Metabolism to Cell Destiny

Metal ions are indispensable for cellular life, as they maintain mitochondrial ion homeostasis and function as essential cofactors in mitochondrial energy metabolism, particularly within the electron transport chain (ETC) and the tricarboxylic acid (TCA) cycle. Disruption of metal ion homeostasis, however, can precipitate excessive reactive oxygen species (ROS) generation, collapse of the mitochondrial membrane potential (ΔΨm), and failure of cellular energy supply. These events ultimately culminate in mitochondrial dysfunction and trigger multiple metal ion-dependent cell death pathways, including ferroptosis, copper-induced cell death, and sodium-dependent cell death. By integrating recent advances in metallomics and mitochondrial biology, this review summarizes the roles of six key metal ions-iron (Fe²⁺), copper (Cu⁺), sodium (Na⁺), calcium (Ca²⁺), zinc (Zn²⁺), and magnesium (Mg²⁺)-in mitochondrial energy metabolism and the regulation of cell fate. Emerging evidence indicates that metal ions are not merely metabolic cofactors but also act as critical signalling switches that determine cellular survival or death through modulation of mitochondrial bioenergetics, redox balance, and ion homeostasis. A deeper understanding of metal ion-dependent mitochondrial dysfunction and associated cell death mechanisms provides a robust theoretical framework for elucidating the pathogenesis of cancer, neurodegenerative disorders, and cardiovascular diseases, and may facilitate the development of novel therapeutic strategies targeting mitochondrial metal ion homeostasis.