Decline of phosphotransfer and substrate supply metabolic circuits hinders ATP cycling in aging myocardium

Emirhan Nemutlu, Anu Gupta, Song Zhang, Maria Viqar, Ekhson Holmuhamedov, Andre Terzic, Arshad Jahangir, Petras P Dzeja

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Integration of mitochondria with cytosolic ATP-consuming/ATP-sensing and substrate supply processes is critical for muscle bioenergetics and electrical activity. Whether age-dependent muscle weakness and increased electrical instability depends on perturbations in cellular energetic circuits is unknown. To define energetic remodeling of aged atrial myocardium we tracked dynamics of ATP synthesis-utilization, substrate supply, and phosphotransfer circuits through adenylate kinase (AK), creatine kinase (CK), and glycolytic/glycogenolytic pathways using 18O stable isotope-based phosphometabolomic technology. Samples of intact atrial myocardium from adult and aged rats were subjected to 18O-labeling procedure at resting basal state, and analyzed using the 18O-assisted HPLC-GC/MS technique. Characteristics for aging atria were lower inorganic phosphate Pi[18O], γ-ATP[18O], β-ADP[18O], and creatine phosphate CrP[18O] 18O-labeling rates indicating diminished ATP utilization-synthesis and AK and CK phosphotransfer fluxes. Shift in dynamics of glycolytic phosphotransfer was reflected in the diminished G6P[18O] turnover with relatively constant glycogenolytic flux or G1P[18O] 18O-labeling. Labeling of G3P[18O], an indicator of G3Pshuttle activity and substrate supply to mitochondria, was depressed in aged myocardium. Aged atrial myocardium displayed reduced incorporation of 18O into second (18O2), third (18O3), and fourth (18O4) positions of Pi[18O] and a lower Pi[18O]/γ-ATP[18 O]-labeling ratio, indicating delayed energetic communication and ATP cycling between mitochondria and cellular ATPases. Adrenergic stress alleviated diminished CK flux, AK catalyzed β-ATP turnover and energetic communication in aging atria. Thus, 18O-assisted phosphometabolomics uncovered simultaneous phosphotransfer through AK, CK, and glycolytic pathways and G3P substrate shuttle deficits hindering energetic communication and ATP cycling, which may underlie energetic vulnerability of aging atrial myocardium.

Original languageEnglish (US)
Article numbere0136556
JournalPLoS One
Volume10
Issue number9
DOIs
StatePublished - Sep 17 2015

Fingerprint

adenylate kinase
myocardium
creatine kinase
Myocardium
Adenosine Triphosphate
Aging of materials
Adenylate Kinase
Networks (circuits)
Substrates
Creatine Kinase
Labeling
mitochondria
glycolysis
Mitochondria
animal communication
phosphates
Communication
muscles
creatine
synthesis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Decline of phosphotransfer and substrate supply metabolic circuits hinders ATP cycling in aging myocardium. / Nemutlu, Emirhan; Gupta, Anu; Zhang, Song; Viqar, Maria; Holmuhamedov, Ekhson; Terzic, Andre; Jahangir, Arshad; Dzeja, Petras P.

In: PLoS One, Vol. 10, No. 9, e0136556, 17.09.2015.

Research output: Contribution to journalArticle

Nemutlu, Emirhan ; Gupta, Anu ; Zhang, Song ; Viqar, Maria ; Holmuhamedov, Ekhson ; Terzic, Andre ; Jahangir, Arshad ; Dzeja, Petras P. / Decline of phosphotransfer and substrate supply metabolic circuits hinders ATP cycling in aging myocardium. In: PLoS One. 2015 ; Vol. 10, No. 9.
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AU - Nemutlu, Emirhan

AU - Gupta, Anu

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AU - Terzic, Andre

AU - Jahangir, Arshad

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