The compartmentalisation of distinct organelles within eukaryotic cells is essential for their diverse functions. However, how their structures and functions depend on each other has not been systematically explored. We combined a fluorescent reporter of mitochondrial stress with genome-wide CRISPR knockout screening and identified networks of genes involved in biogenesis and metabolism of diverse organelles. Targeted organelle gene knockouts identified common defects that cause mitochondrial dysfunction. Correlative light and electron microscopy analysed using artificial intelligence-directed voxel extraction revealed in unprecedented detail how impaired mitochondrial interactions with organelles caused cell-wide defects in their morphology and biogenesis. Multi-omics analyses identified a unified proteome response and global shifts in metabolism that are elicited when organelle biogenesis is compromised. I will discuss the metabolic and morphological interactions between organelles that can be mined to understand how changes in organelle components drive diverse cellular pathologies.