Embryos of the brine shrimp Artemia franciscana are able to withstand bouts of environmental anoxia for several years by entering a quiescent state, during which time metabolism is greatly depressed. Within minutes of oxygen removal, intracellular pH (pHi) drops at least 1.0 unit. This acidification has been strongly implicated in the arrest of both catabolic and anabolic processes in the cytoplasm. A global arrest of cytoplasmic translation accompanies the transition into anoxia or into aerobic acidosis (artificial quiescence imposed by intracellular acidification with CO2 in the presence of oxygen). Similarly, protein synthesis in isolated mitochondria from these embryos is also reduced markedly in response to acidic pH (80% reduction) or anoxia (79% reduction). The constancy of mRNA levels during quiescence indicates that protein synthesis is likely to be controlled at the translational level. Mitochondrial matrix pH is 8.2 during protein synthesis assays performed at the extramitochondrial pH optimum of 7.5. When this proton gradient is abolished with the K+/H+ ionophore nigericin, the extramitochondrial pH optimum for protein synthesis displays an alkaline shift of approximately 0.7 pH unit. These data suggest the presence of proton-sensitive translational components within the mitochondrion. The oxygen dependency of mitochondrial protein synthesis is not explained simply by blockage of the electron transport chain or by the increased redox state. Whereas oxygen deprivation substantially depresses protein synthesis by 77% after 1 h, normoxic incubations with saturating concentrations of cyanide or antimycin A have only a modest effect (36% reduction, cyanide; 20%, antimycin A). This cyanide- and antimycin-insensitive, but hypoxia-sensitive, inhibitory signature for the arrest of protein synthesis suggests the presence of a molecular oxygen sensor within the mitochondrion.