Calcium and bicarbonate signaling pathways have pivotal, resonating roles in matching ATP production to demand.

Autor: Greiser M; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States.; Department of Physiology, University of Marylan School of Medicine, Baltimore, United States.; Claude D. Pepper Older Americans Independence Center, University of Maryland School of Medicine, Baltimore, United States., Karbowski M; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States.; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, United States.; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Baltimore School of Medicine, Baltimore, United States., Kaplan AD; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States.; Division of Cardiovascular Medicine, Department of Medicine, University of Maryland School of Medicine, Baltimore, United States., Coleman AK; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States.; Department of Physiology, University of Marylan School of Medicine, Baltimore, United States., Verhoeven N; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States.; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, United States., Mannella CA; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States.; Department of Physiology, University of Marylan School of Medicine, Baltimore, United States., Lederer WJ; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States.; Department of Physiology, University of Marylan School of Medicine, Baltimore, United States.; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Baltimore School of Medicine, Baltimore, United States., Boyman L; Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, United States.; Department of Physiology, University of Marylan School of Medicine, Baltimore, United States.; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Baltimore School of Medicine, Baltimore, United States.
Jazyk: angličtina
Zdroj: ELife [Elife] 2023 Jun 05; Vol. 12. Date of Electronic Publication: 2023 Jun 05.
DOI: 10.7554/eLife.84204
Abstrakt: Mitochondrial ATP production in ventricular cardiomyocytes must be continually adjusted to rapidly replenish the ATP consumed by the working heart. Two systems are known to be critical in this regulation: mitochondrial matrix Ca 2+ ([Ca 2+ ] m ) and blood flow that is tuned by local cardiomyocyte metabolic signaling. However, these two regulatory systems do not fully account for the physiological range of ATP consumption observed. We report here on the identity, location, and signaling cascade of a third regulatory system -- CO 2 /bicarbonate. CO 2 is generated in the mitochondrial matrix as a metabolic waste product of the oxidation of nutrients. It is a lipid soluble gas that rapidly permeates the inner mitochondrial membrane and produces bicarbonate in a reaction accelerated by carbonic anhydrase. The bicarbonate level is tracked physiologically by a bicarbonate-activated soluble adenylyl cyclase (sAC). Using structural Airyscan super-resolution imaging and functional measurements we find that sAC is primarily inside the mitochondria of ventricular cardiomyocytes where it generates cAMP when activated by bicarbonate. Our data strongly suggest that ATP production in these mitochondria is regulated by this cAMP signaling cascade operating within the inter-membrane space by activating local EPAC1 ( E xchange P rotein directly A ctivated by c AMP) which turns on Rap1 (Ras-related protein-1). Thus, mitochondrial ATP production is increased by bicarbonate-triggered sAC-signaling through Rap1. Additional evidence is presented indicating that the cAMP signaling itself does not occur directly in the matrix. We also show that this third signaling process involving bicarbonate and sAC activates the mitochondrial ATP production machinery by working independently of, yet in conjunction with, [Ca 2+ ] m -dependent ATP production to meet the energy needs of cellular activity in both health and disease. We propose that the bicarbonate and calcium signaling arms function in a resonant or complementary manner to match mitochondrial ATP production to the full range of energy consumption in ventricular cardiomyocytes.
Competing Interests: MG, MK, AK, AC, NV, CM, WL, LB No competing interests declared
(© 2023, Greiser, Karbowski et al.)
Databáze: MEDLINE
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