FASEB J. 2007 Jan 3; [Epub ahead of print]
Uncoupling protein-3: clues in an ongoing mitochondrial mystery.
Bezaire V, Seifert EL, Harper ME.
Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine,
University of Ottawa, Ottawa, Ontario, Canada.
Uncoupling protein (UCP) 3 (UCP3) is a mitochondrial anion carrier protein with
highly selective expression in skeletal muscle. Despite a great deal of
interest, to date neither its molecular mechanism nor its biochemical and
physiological functions are well understood. Based on its high degree of
homology to the original UCP (UCP1), early studies examined a role for UCP3 in
thermogenesis. However, evidence for such a function is lacking. Recent studies
have focused on two distinct, but not mutually exclusive, hypotheses: 1) UCP3
mitigates reactive oxygen species (ROS) production, and 2) UCP3 is somehow
involved in fatty acid (FA) translocation. While supportive evidence exists for
both hypotheses, the interpretation of the corresponding evidence has created
some controversy. Mechanistic studies examining mitigated ROS production have
been largely conducted in vitro, and the physiological significance of the
findings is questioned. Conversely, while physiological evidence exists for FA
translocation hypotheses, the evidence is largely correlative, leaving causal
relationships unexplored. This review critically assesses evidence for the
hypotheses and attempts to link the outcomes from mechanistic studies to
physiological implications. Important directions for future studies, using
current and novel approaches, are discussed.--Bezaire V., Seifert E. L., Harper
M-E. Uncoupling protein-3: clues in an ongoing mitochondrial mystery.