Near-Native Imagingof Metal Ion-Initiated Cell StateTransition

Metal ions are indispensable to life, as they can serve as essential enzyme cofactors to drive fundamental biochemical reactions, yet paradoxically, excess is highly toxic. Higher-order cells have evolved functionally distinct organelles that separate and coordinate sophisticated biochemical processes to maintain cellular homeostasis upon metal ion stimuli. Here, we uncover the remodeling of subcellular architecture and organellar interactome in yeast initiated by several metal ion stimulations, relying on near-native three-dimensional imaging, cryo-soft X-ray tomography. The three-dimensional architecture of intact yeast directly shows that iron or manganese triggers a hormesis-like effect that promotes cell proliferation. This process leads to the reorganization of organelles in the preparation for division, characterized by the polar distribution of mitochondria, an increased number of lipid droplets (LDs), volume shrinkage, and the formation of a hollow structure. Additionally, vesicle-like structures that detach from the vacuole are observed. Oppositely, cadmium or mercury causes stress-associated phenotypes, including mitochondrial fragmentation, LD swelling, and autophagosome formation. Notably, the organellar interactome, encompassing the interactions between mitochondria and LDs and those between the nuclear envelope and LDs, is quantified and exhibits alteration with multifaceted features in response to different metal ions. More importantly, the dynamics of organellar architecture render them more sensitive biomarkers than traditional approaches for assessing the cell state. Strikingly, yeast has a powerful depuration capacity to isolate and transform the overaccumulated cadmium in the vacuole, mitochondria, and cytoplasm as a high-value product, quantum dots. This work presents the possibility of discovering fundamental links between organellar morphological characteristics and the cell state.