Mitochondrial DNA (mtDNA) depletion syndromes are generally associated with reduced activities of oxidative phosphorylation (OXPHOS) enzymes that contain subunits encoded by mtDNA. Conversely, entirely nuclear encoded mitochondrial enzymes in these syndromes, such as the tricarboxylic acid cycle enzyme citrate synthase (CS) and OXPHOS complex II, usually exhibit normal or compensatory enhanced activities. Here we report that a human cell line devoid of mtDNA (HEK293 rho(0) cells) has diminished activities of both complex II and CS. This finding indicates the existence of a feedback mechanism in rho(0) cells that downregulates the expression of entirely nuclear encoded components of mitochondrial energy metabolism. (C) 2011 Elsevier Inc. All rights reserved.