Active control of mitochondrial network morphology by metabolism driven redox state

Mitochondria are dynamic organelles that change in morphology in different environments. What controls the mitochondrial morphology remains unresolved. Using yeast cells grown in distinct carbon environments requiring mitochondrial respiration, we find that mitochondrial morphology and activity are unrelated. Cells show fragmented as well as networked mitochondrial networks in nutrient environments with high or low mitochondrial activity. Resolving this paradox, we find that mitochondrial morphology is controlled by the intracellular redox state, which depends on the nature of electron entry into the Electron Transport Chain. In conditions with high direct electron entry, reactive oxygen species increase and the cytosolic environment becomes oxidized, leading to rapid mitochondrial fragmentation. Using genetic approaches to reduce electron injection into the ETC, we restore networked morphologies. Using pharmacologic agents to disrupt electron flow, or alter redox state, we demonstrate minute-scale, activity-independent control between networked and fragmented forms. Mitochondria thus actively control their morphology by regulating redox state.