Adenylate Kinase Isoform Network: A Major Hub in Cell Energetics and Metabolic Signaling - Systems Biology of Metabolic and Signaling Networks - page 141

Chapter 6
Adenylate Kinase Isoform Network: A Major
Hub in Cell Energetics and Metabolic
Signaling
Song Zhang, Emirhan Nemutlu, Andre Terzic, and Petras Dzeja
Abstract The adenylate kinase isoform network is integral to the cellular energetic
system and a major player in AMP metabolic signaling circuits. Critical in energy
state monitoring and stress response, the dynamic behavior of the adenylate kinase
network in governing intracellular, nuclear, and extracellular nucleotide signaling
processes has been increasingly revealed. New adenylate kinase mutations have been
identified that cause severe human disease phenotypes such as reticular dysgenesis
associated with immunodeficiency and sensorineural hearing loss and primary ciliary
dyskinesia characteristic of chronic obstructive pulmonary disease. The adenylate
kinase family comprises nine major isoforms (AK1-AK9), and several subforms with
distinct intracellular localization and kinetic properties designed to support specific
cellular processes ranging from muscle contraction, electrical activity, cell motility,
unfolded protein response, and mitochondrial/nuclear energetics. Adenylate kinase
and AMP signaling is necessary for energetic communication between mitochondria,
myofibrils, and the cell nucleus and for metabolic programming facilitating stem cell
cardiac differentiation and mitochondrial network formation. Moreover, it was
discovered that during cell cycle, the AK1 isoform translocates to the nucleus and
associates with the mitotic spindle to provide energy for cell division. Furthermore,
deletion of Ak2 gene is embryonically lethal, indicating critical significance of
catalyzed phosphotransfer in the crowded mitochondrial intracristae and subcellular
spaces for ATP export and intracellular distribution. Taken together, new evidence
highlights the importance of the system-wide adenylate kinase isoform network and
adenylate kinase-mediated phosphotransfer and AMP signaling in cellular energetics,
metabolic sensing, and regulation of nuclear and cell cycle processes which are
critical in tissue homeostasis, renewal, and regeneration.
S. Zhang • A. Terzic • P. Dzeja ( * )
Center for Regenerative Medicine, Division of Cardiovascular Diseases, Department of
Medicine, Mayo Clinic, Rochester, MN 55905, USA
e-mail: [e-mail]
E. Nemutlu
Analytical Chemistry, Hacettepe University, Ankara, Turkey