How the Topology of the Mitochondrial Inner Membrane Modulates ATP Production
Cells in heart muscle need to generate ATP at or near peak capacity to meet their energy demands. Over 90% of this ATP comes from mitochondria, strategically located near myofibrils and densely packed with cristae to concentrate ATP generation per unit volume. However, a consequence of dense inner m...
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MDPI AG
2025-02-01
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| author | Raquel Adams Nasrin Afzal Mohsin Saleet Jafri Carmen A. Mannella |
| author_facet | Raquel Adams Nasrin Afzal Mohsin Saleet Jafri Carmen A. Mannella |
| author_sort | Raquel Adams |
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| description | Cells in heart muscle need to generate ATP at or near peak capacity to meet their energy demands. Over 90% of this ATP comes from mitochondria, strategically located near myofibrils and densely packed with cristae to concentrate ATP generation per unit volume. However, a consequence of dense inner membrane (IM) packing is that restricted metabolite diffusion inside mitochondria may limit ATP production. Under physiological conditions, the flux of ATP synthase is set by ADP levels in the matrix, which in turn depends on diffusion-dependent concentration of ADP inside cristae. Computer simulations show how ADP diffusion and consequently rates of ATP synthesis are modulated by IM topology, in particular (i) number, size, and positioning of crista junctions that connect cristae to the IM boundary region, and (ii) branching of cristae. Predictions are compared with the actual IM topology of a cardiomyocyte mitochondrion in which cristae vary systematically in length and morphology. The analysis indicates that this IM topology decreases but does not eliminate the “diffusion penalty” on ATP output. It is proposed that IM topology normally attenuates mitochondrial ATP output under conditions of low workload and can be regulated by the cell to better match ATP supply to demand. |
| format | Article |
| id | doaj-art-ecfb98d8fdd24e06a7d6df50a43b1ac9 |
| institution | DOAJ |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | MDPI AG |
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| series | Cells |
| spelling | doaj-art-ecfb98d8fdd24e06a7d6df50a43b1ac92025-08-20T03:12:14ZengMDPI AGCells2073-44092025-02-0114425710.3390/cells14040257How the Topology of the Mitochondrial Inner Membrane Modulates ATP ProductionRaquel Adams0Nasrin Afzal1Mohsin Saleet Jafri2Carmen A. Mannella3School of Systems Biology, George Mason University, Fairfax, VA 22030, USASchool of Systems Biology, George Mason University, Fairfax, VA 22030, USASchool of Systems Biology, George Mason University, Fairfax, VA 22030, USACenter for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD 20201, USACells in heart muscle need to generate ATP at or near peak capacity to meet their energy demands. Over 90% of this ATP comes from mitochondria, strategically located near myofibrils and densely packed with cristae to concentrate ATP generation per unit volume. However, a consequence of dense inner membrane (IM) packing is that restricted metabolite diffusion inside mitochondria may limit ATP production. Under physiological conditions, the flux of ATP synthase is set by ADP levels in the matrix, which in turn depends on diffusion-dependent concentration of ADP inside cristae. Computer simulations show how ADP diffusion and consequently rates of ATP synthesis are modulated by IM topology, in particular (i) number, size, and positioning of crista junctions that connect cristae to the IM boundary region, and (ii) branching of cristae. Predictions are compared with the actual IM topology of a cardiomyocyte mitochondrion in which cristae vary systematically in length and morphology. The analysis indicates that this IM topology decreases but does not eliminate the “diffusion penalty” on ATP output. It is proposed that IM topology normally attenuates mitochondrial ATP output under conditions of low workload and can be regulated by the cell to better match ATP supply to demand.https://www.mdpi.com/2073-4409/14/4/257mitochondriacristaeelectron tomographymetabolic modelingmembrane topologymetabolite diffusion |
| spellingShingle | Raquel Adams Nasrin Afzal Mohsin Saleet Jafri Carmen A. Mannella How the Topology of the Mitochondrial Inner Membrane Modulates ATP Production Cells mitochondria cristae electron tomography metabolic modeling membrane topology metabolite diffusion |
| title | How the Topology of the Mitochondrial Inner Membrane Modulates ATP Production |
| title_full | How the Topology of the Mitochondrial Inner Membrane Modulates ATP Production |
| title_fullStr | How the Topology of the Mitochondrial Inner Membrane Modulates ATP Production |
| title_full_unstemmed | How the Topology of the Mitochondrial Inner Membrane Modulates ATP Production |
| title_short | How the Topology of the Mitochondrial Inner Membrane Modulates ATP Production |
| title_sort | how the topology of the mitochondrial inner membrane modulates atp production |
| topic | mitochondria cristae electron tomography metabolic modeling membrane topology metabolite diffusion |
| url | https://www.mdpi.com/2073-4409/14/4/257 |
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