The structures and functions of organelles in cells depend on each other but have not been systematically explored. We established stable knockout cell lines of peroxisomal, Golgi and endoplasmic reticulum genes identified in a whole-genome CRISPR knockout screen for inducers of mitochondrial biogenesis stress, showing that defects in peroxisome, Golgi and endoplasmic reticulum metabolism cause a convergent disruption to mitochondrial structure and function. Our quantitative total-organelle profiling approach for focussed ion beam scanning electron microscopy revealed in unprecedented detail that specific organelle dysfunctions precipitate multi-organelle biogenesis defects, impair mitochondrial morphology regulation, and reduce oxidative phosphorylation capacity. Multi-omics profiling showed a unified proteome response and global shifts in lipid and glycoprotein homeostasis that are elicited when organelle biogenesis is compromised. We further highlighted that deficiencies in ether lipid biosynthesis was a key metabolic feature underlying the mitochondrial dysfunction across the peroxisomal, Golgi, and endoplasmic reticular dysfunction cell lines. We targeted the ether lipid pathway with therapeutic precursor compounds called alkylglycerols, which restored ether lipid levels and rescued the defects in mitochondrial structure and function in all cell lines. This work defines metabolic and morphological interactions between organelles and how their perturbation can cause disease, and established that ether lipid metabolism can be targeted as a potential method for future management of pathologies relating to a breakdown in organelle function and communication.