PMID- 34954465 OWN - NLM STAT- MEDLINE DCOM- 20220510 LR - 20230402 IS - 1095-8584 (Electronic) IS - 0022-2828 (Print) IS - 0022-2828 (Linking) VI - 165 DP - 2022 Apr TI - Computational modeling of mitochondrial K(+)- and H(+)-driven ATP synthesis. PG - 9-18 LID - S0022-2828(21)00232-7 [pii] LID - 10.1016/j.yjmcc.2021.12.005 [doi] AB - ATP synthase (F(1)F(o)) is a rotary molecular engine that harnesses energy from electrochemical-gradients across the inner mitochondrial membrane for ATP synthesis. Despite the accepted tenet that F(1)F(o) transports exclusively H(+), our laboratory has demonstrated that, in addition to H(+), F(1)F(o) ATP synthase transports a significant fraction of DeltaPsi(m)-driven charge as K(+) to synthesize ATP. Herein, we utilize a computational modeling approach as a proof of principle of the feasibility of the core mechanism underlying the enhanced ATP synthesis, and to explore its bioenergetic consequences. A minimal model comprising the 'core' mechanism constituted by ATP synthase, driven by both proton (PMF) and potassium motive force (KMF), respiratory chain, adenine nucleotide translocator, Pi carrier, and K(+)/H(+) exchanger (KHEmito) was able to simulate enhanced ATP synthesis and respiratory fluxes determined experimentally with isolated heart mitochondria. This capacity of F(1)F(o) ATP synthase confers mitochondria with a significant energetic advantage compared to K(+) transport through a channel not linked to oxidative phosphorylation (OxPhos). The K(+)-cycling mechanism requires a KHE(mito) that exchanges matrix K(+) for intermembrane space H(+), leaving PMF as the overall driving energy of OxPhos, in full agreement with the standard chemiosmotic mechanism. Experimental data of state 4➔3 energetic transitions, mimicking low to high energy demand, could be reproduced by an integrated computational model of mitochondrial function that incorporates the 'core' mechanism. Model simulations display similar behavior compared to the experimentally observed changes in DeltaPsi(m), mitochondrial K(+) uptake, matrix volume, respiration, and ATP synthesis during the energetic transitions at physiological pH and K(+) concentration. The model also explores the role played by KHE(mito) in modulating the energetic performance of mitochondria. The results obtained support the available experimental evidence on ATP synthesis driven by K(+) and H(+) transport through the F(1)F(o) ATP synthase. CI - Copyright (c) 2021. Published by Elsevier Ltd. FAU - Cortassa, Sonia AU - Cortassa S AD - Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States of America. Electronic address: sonia.cortassa@nih.gov. FAU - Aon, Miguel A AU - Aon MA AD - Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States of America. Electronic address: miguel.aon@nih.gov. FAU - Juhaszova, Magdalena AU - Juhaszova M AD - Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States of America. Electronic address: juhaszovam@mail.nih.gov. FAU - Kobrinsky, Evgeny AU - Kobrinsky E AD - Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States of America. Electronic address: KobrinskiEv@grc.nia.nih.gov. FAU - Zorov, Dmitry B AU - Zorov DB AD - Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States of America; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia. Electronic address: Zorovd@mail.nih.gov. FAU - Sollott, Steven J AU - Sollott SJ AD - Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States of America. Electronic address: Sollotts@mail.nih.gov. LA - eng GR - Z99 AG999999/ImNIH/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural DEP - 20211223 PL - England TA - J Mol Cell Cardiol JT - Journal of molecular and cellular cardiology JID - 0262322 RN - 0 (Protons) RN - 8L70Q75FXE (Adenosine Triphosphate) RN - EC 3.6.3.- (Mitochondrial Proton-Translocating ATPases) RN - RWP5GA015D (Potassium) SB - IM MH - Adenosine Triphosphate MH - Computer Simulation MH - Mitochondria, Heart/metabolism MH - *Mitochondrial Membranes/metabolism MH - Mitochondrial Proton-Translocating ATPases/metabolism MH - Potassium/*metabolism MH - *Protons PMC - PMC8940703 MID - NIHMS1779283 OTO - NOTNLM OT - Energy supply-demand matching OT - F(1)F(o) ATP synthase OT - Mitochondrial K(+) uptake OT - Mitochondrial K(+)/H(+) exchanger EDAT- 2021/12/27 06:00 MHDA- 2022/05/11 06:00 PMCR- 2023/04/01 CRDT- 2021/12/26 20:46 PHST- 2021/03/18 00:00 [received] PHST- 2021/09/20 00:00 [revised] PHST- 2021/12/06 00:00 [accepted] PHST- 2021/12/27 06:00 [pubmed] PHST- 2022/05/11 06:00 [medline] PHST- 2021/12/26 20:46 [entrez] PHST- 2023/04/01 00:00 [pmc-release] AID - S0022-2828(21)00232-7 [pii] AID - 10.1016/j.yjmcc.2021.12.005 [doi] PST - ppublish SO - J Mol Cell Cardiol. 2022 Apr;165:9-18. doi: 10.1016/j.yjmcc.2021.12.005. Epub 2021 Dec 23.