Mitochondrial Creatine Kinase is Critically Necessary to Maintain ...

Introduction
MS H-00800-2001-R1
Creatine kinase (CK, EC 2.7.2.2) is a key enzyme involved in energy metabolism in tissues with
large fluctuations of energetic demand such as muscle or brain. CK catalyses the reversible
transfer of a high-energy phosphoryl group between ATP and phosphocreatine (PCr). Four
different isoenzymes of CK are known, three are dimers composed of 2 subunits (MM-CK, MB-
CK and BB-CK), whereas sarcomeric mitochondrial CK (ScCKmit) can form both dimers and
octamers (for review see (28)). These isoenzymes are localized in a compartimentalized fashion
in the cell. MM-CK, the most abundant muscle isoform, is a structural protein of the myofibrillar
M-band. ScCKmit, the second most abundant isoform, is found on the outer surface of the inner
mitochondrial membrane forming a functional compartment with porin and the adenine
nucleotide translocase (29). This characteristic spacial distribution has led to the “CK shuttle”
hypothesis, where PCr serves as an energy transfer molecule for fast and efficient transport of
phosphoryl moieties from the sites of energy generation (mitochondria) to the sites of energy
consumption (myofibrils and ion pumps) (1). On the other hand, the PCr-CK system has been
generally regarded as a high-energy buffer system, that meets increased energetic requirements
during periods of mismatched energy production and consumption. The physiological
importance of the CK system in heart muscle is underlined by numerous reports of alterations in
a variety of components of the PCr-CK system found in various animal models of heart failure as
well as in human heart failure (10, 12-14).
Despite several decades of research, however, the true nature of the fundamental role of CK,
especially in disease states such as myopathies or heart failure, remains ill-defined. Transgenic
animals with null mutations of one or more of the genes of the CK family may shed new light on
the functional significance of the PCr-CK system. For example, skeletal muscle of mice lacking
the M-subunit of CK, referred to here as M-CK -/- , demonstrate a transient impairment in
contractile function (burst activity) (25). However, concentrations of high-energy phosphate
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