Mitochondria have their own unique gene expression system that has diverged dramatically since the original endosymbiotic event that created eukaryotes. The fidelity of gene expression is crucial in prokaryotes and for the nuclear-encoded proteins of eukaryotes, however little is known about its role in mitochondria and its effects on metabolism. We have generated mouse models to understand the importance of mitochondrial gene expression for cell function in mammals. We have found diverse tissue-specific pathologies that activate different stress signalling pathways, alter metabolism and manifest in diverse disease phenotypes. Our findings highlight the importance of mitochondrial function in many different diseases and their myriad roles in normal cellular biology.