Abstract P242: Adenylate Kinase 2 Deficiency Disrupts Mitochondrial Energetics, AMP Metabolic Signaling, and Metabolomic Response to Myocardial Stress

Abstract

Adenylate kinase 2 (AK2) isoform in mitochondrial intermembrane/intracristal space provides a conduit facilitating ATP export and delivery to cellular ATPases. AK2+/- transgenic mice is viable while homozygous AK2-/- deficiency results in midgestation embryonic lethality. AK2-/- mouse embryonic fibroblasts (MEFs) have severely disrupted mitochondrial cristae structure and display low growth and proliferation potential. Protein knockdown using siRNA indicates that AK2 is critical for cardiomyocyte mitochondrial biogenesis and network formation. Transgenic AK2+/- hearts display greater changes in AMP/ATP ratio and AMPK activation during ischemia compared to wild type suggesting deficient tuning of AMP signals. Metabolomic profile of AK2+/- hearts subjected to myocardial ischemia indicate lower ability to maintain adenine and guanine nucleotide pools. AK2+/- mice have abnormal metabolomic response to treadmill exercise compared to wild type. Metabolomic profiling revealed that most significant plasma metabolites critical in the discrimination between wild type and AK2+/- phenotypes were adenosine, tyrosine, tryptophan and hypoxanthine indicating lower energetic potential of AK2+/- mice. AK2+/- hearts have increased mitochondrial creatine kinase CKmit content which could be viewed as a compensatory mechanism. Thus, AK2 is the first phosphotransfer enzyme which deficiency causes embryonic lethality indicating critical significance of catalyzed nucleotide exchange and conductive transfer in the narrow and crowded mitochondrial intermembrane/intracristal space.