TY - JOUR
T1 - Adenylate kinase AK2 isoform integral in embryo and adult heart homeostasis
AU - Zhang, Song
AU - Yamada, Satsuki
AU - Park, Sungjo
AU - Klepinin, Aleksandr
AU - Kaambre, Tuuli
AU - Terzic, Andre
AU - Dzeja, Petras
N1 - Funding Information:
Authors acknowledge support from the National Institutes of Health ( R01 HL134664 and R01 HL85744 ), Marriott Family Foundation, Van Cleve Cardiac Regenerative Medicine Program, Michael S. and Mary Sue Shannon Family, and Center for Regenerative Medicine at Mayo Clinic , as well as Kristjan Jaak Scholarship Programme (Estonian Ministry of Education and Research in collaboration with Archimedes Foundation ).
Publisher Copyright:
© 2021 The Authors
PY - 2021/3/26
Y1 - 2021/3/26
N2 - Adenylate kinase2 (AK2) catalyzes trans-compartmental nucleotide exchange, but the functional implications of this mitochondrial intermembrane isoform is only partially understood. Here, transgenic AK2−/− null homozygosity was lethal early in embryo, indicating a mandatory role for intact AK2 in utero development. In the adult, conditional organ-specific ablation of AK2 precipitated abrupt heart failure with Krebs cycle and glycolytic metabolite buildup, suggesting a vital contribution to energy demanding cardiac performance. Depressed pump function recovered to pre-deletion levels overtime, suggestive of an adaptive response. Compensatory upregulation of phosphotransferase AK1, AK3, AK4 isozymes, creatine kinase isoforms, and hexokinase, along with remodeling of cell cycle/growth genes and mitochondrial ultrastructure supported organ rescue. Taken together, the requirement of AK2 in early embryonic stages, and the immediate collapse of heart performance in the AK2-deficient postnatal state underscore a primordial function of the AK2 isoform. Unsalvageable in embryo, loss of AK2 in the adult heart was recoverable, underscoring an AK2-integrated bioenergetics system with innate plasticity to maintain homeostasis on demand.
AB - Adenylate kinase2 (AK2) catalyzes trans-compartmental nucleotide exchange, but the functional implications of this mitochondrial intermembrane isoform is only partially understood. Here, transgenic AK2−/− null homozygosity was lethal early in embryo, indicating a mandatory role for intact AK2 in utero development. In the adult, conditional organ-specific ablation of AK2 precipitated abrupt heart failure with Krebs cycle and glycolytic metabolite buildup, suggesting a vital contribution to energy demanding cardiac performance. Depressed pump function recovered to pre-deletion levels overtime, suggestive of an adaptive response. Compensatory upregulation of phosphotransferase AK1, AK3, AK4 isozymes, creatine kinase isoforms, and hexokinase, along with remodeling of cell cycle/growth genes and mitochondrial ultrastructure supported organ rescue. Taken together, the requirement of AK2 in early embryonic stages, and the immediate collapse of heart performance in the AK2-deficient postnatal state underscore a primordial function of the AK2 isoform. Unsalvageable in embryo, loss of AK2 in the adult heart was recoverable, underscoring an AK2-integrated bioenergetics system with innate plasticity to maintain homeostasis on demand.
KW - Adaptation
KW - Adenylate kinase
KW - Homeostasis
KW - Knockout
KW - Metabolism
KW - Phosphotransfer
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U2 - 10.1016/j.bbrc.2021.01.097
DO - 10.1016/j.bbrc.2021.01.097
M3 - Article
C2 - 33571905
AN - SCOPUS:85100659350
SN - 0006-291X
VL - 546
SP - 59
EP - 64
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
ER -