Journal of Bioenergetics and Biomembranes, Vol. 30, No. 3, 1998 Human Mitochondrial Transmembrane Metabolite Carriers: Tissue Distribution and Its Implication for Mitochondrial Disorders Marjan Huizing,1 Wim Ruitenbeek,1 Lambert P. van den Heuvel,1 Vincenza Dolce,2 Vito Iacobazzi,2 Jan A. M. Smeitink,1 Ferdinando Palmieri,2 and J. M. Frans Trijbels1 Received December 10, 1997; accepted April 29, 1998 Mitochondrial transmembrane carrier deficiencies are a recently discovered group of disorders, belonging to the so-called mitochondriocytopathies. We examined the human tissue distribution of carriers which are involved in the process of oxidative phosphorylation (adenine nucleotide translocator, phosphate carrier, and voltage-dependent anion channel) and some mitochondrial substrate carriers (2-oxoglutarate carrier, carnitine-acylcarnitine carrier, and citrate carrier). The tissue distribution on mRNA level of mitochondrial transport proteins appears to be roughly in correlation with the dependence of these tissues on mitochondrial energy production capacity. In general the main mRNA expression of carriers involved in mitochondrial energy metabolism occurs in skeletal muscle and heart. Expression in liver and pancreas differs between carriers. Expression in brain, placenta, lung, and kidney is lower than in the other tissues. Western and Northern blotting experiments show a comparable HVDAC1 protein and mRNA distribution for the tested tissues. Patient's studies showed that cultured skin fibroblasts may not be a reliable alternative for skeletal muscle in screening for human mitochondrial carrier defects. KEY WORDS: Mitochondrial transmembrane carrier; tissue distribution; mitochondriopathy; adenine nucleotide translocator; phosphate carrier; voltage-dependent anion channel; citrate carrier; oxoglutarate carrier; carnitine-acylcarnitine carrier. INTRODUCTION When studying mitochondrial disorders it is worthwhile to consider the mitochondrial transmem- brane carriers because a defective functioning of such carriers may lead to a disturbed mitochondrial energy generation (Ruitenbeek et al., 1995; Huizing et al., 1996a). Of particular interest are the carriers which are directly involved in the process of oxidative phos- phorylation, such as the adenine nucleotide transloca- tor (ANT3) and the phosphate carrier (PiC). However, also defects in mitochondrial carriers for transport of specific substrates (such as pyruvate, 2-oxoglutarate, malate, carnitine, and glutamate), directly or indirectly involved in mitochondrial energy metabolism, have to be considered. Many of these carriers have been iso- lated and some of them have been cloned and sequenced (Palmieri, 1994; Palmieri and Van Ommen, 1998). Defects in transmembrane cation transporters may also induce imperfect energy metabolism proba- bly as a result of osmotic disturbances within the mito- 1 Department of Pediatrics, University Hospital, Nijmegen, The Netherlands. 2 Department of Pharmaco-Biology, University of Bari, Bari, Italy. 3 Abbreviations used: ANT, adenine nucleotide translocator; bp, base pairs; CAC, carnitine-acylcarnitine carrier; CIC, citrate car- rier; HVDAC, human voltage-dependent anion channel; Mi-CK, mitochondrial creatine kinase; OGC, 2-oxoglutarate carrier; PiC, phosphate carrier. 277 0145-479X/98/0600-0277$l5.00/0 © 1998 Plenum Publishing Corporation