Mitonuclear protein imbalance can be elicited by various mechanisms, including mtDNA mutation, mitochondrial translational inhibition or nuclear gene repression, and may contribute to the longevity of many species.(47) The mitochondrial translation inhibitor doxycycline (DOX) and other tetracyclines also cause ATF4 activation in various cancer cells.(48,49) Bao et al.(50) demonstrated that mitochondrial DNA depletion, induced by the expression of a dominant negative DNA polymerase γ mutant or ethidium bromide, activates ATF4 in HEK293 cells. Here, ATF4 is linked to cancer.