Mitochondria morphology governs ATP production rate

García, Guadalupe C.; Bartol, Thomas M.; Sejnowski, Terrence J.; Rangamani, Padmini

doi:10.1101/2022.08.16.500715

Cited by 3 publications

(7 citation statements)

References 56 publications

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“…We solve the reactions (detailed below) using MCell 163 to accurately capture the stochastic nature of the events underlying ATP production in the small volumes of the mitochondria. The model has a total of 19 equations and 41 parameters and the thermodynamic details are given in 159 . We briefly describe the main components of the model below.…”

Section: Supplementary Information and Methodsmentioning

confidence: 99%

“…The computational for ATP generation in mitochondria is based on previous modeling efforts 97,[159][160][161][162] . We solve the reactions (detailed below) using MCell 163 to accurately capture the stochastic nature of the events underlying ATP production in the small volumes of the mitochondria.…”

Section: Atp Production Modelingmentioning

confidence: 99%

“…The computational for ATP generation in mitochondria is based on previous modeling efforts (Garcia et al , 2019(Garcia et al , , 2022Magnus & Keizer, 1997;Bertram et al , 2006;Saa & Siqueira, 2013) . We solve the reactions (detailed below) using MCell (Kerr et al , 2008) to accurately capture the stochastic nature of the events underlying ATP production in the small volumes of the mitochondria.…”

Section: Atp Production Modelingmentioning

confidence: 99%

“…The model has a total of 19 equations and 41 parameters and the thermodynamic details are given in (Garcia et al , 2022) . We briefly describe the main components of the model below.…”

Section: Atp Production Modelingmentioning

confidence: 99%

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Cristae formation is a mechanical buckling event controlled by the inner membrane lipidome

Venkatraman

Lee

García

et al. 2023

Preprint

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The inner mitochondrial membrane (IMM) is the site of bulk ATP generation in cells and has a broadly conserved lipid composition enriched in unsaturated phospholipids and cardiolipin (CL). While proteins that shape the IMM and its characteristic cristae membranes (CM) have been defined, specific mechanisms by which mitochondrial lipids dictate its structure and function have yet to be elucidated. Here we combine experimental lipidome dissection with multi-scale modeling to investigate how lipid interactions shape CM morphology and ATP generation. When modulating fatty acid unsaturation in engineered yeast strains, we observed that loss of di-unsaturated phospholipids (PLs) led to a breakpoint in IMM topology and respiratory capacity. We found that PL unsaturation modulates the organization of ATP synthases that shape cristae ridges. Based on molecular modeling of mitochondrial-specific membrane adaptations, we hypothesized that conical lipids like CL buffer against the effects of saturation on the IMM. In cells, we discovered that loss of CL collapses the IMM at intermediate levels of PL saturation, an effect that is independent of ATP synthase oligomerization. To explain this interaction, we employed a continuum modeling approach, finding that lipid and protein-mediated curvatures are predicted to act in concert to form curved membranes in the IMM. The model highlighted a snapthrough instability in cristae tubule formation, which could drive IMM collapse upon small changes in composition. The interaction between CL and di-unsaturated PLs suggests that growth conditions that alter the fatty acid pool, such as oxygen availability, could define CL function. While loss of CL only has a minimal phenotype under standard laboratory conditions, we show that its synthesis is essential under microaerobic conditions that better mimic natural yeast fermentation. Lipid and protein-mediated mechanisms of curvature generation can thus act together to support mitochondrial architecture under changing environments.

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Section: Supplementary Information and Methodsmentioning

confidence: 99%

Section: Atp Production Modelingmentioning

confidence: 99%

Section: Atp Production Modelingmentioning

confidence: 99%

“…The model has a total of 19 equations and 41 parameters and the thermodynamic details are given in (Garcia et al , 2022) . We briefly describe the main components of the model below.…”

Section: Atp Production Modelingmentioning

confidence: 99%

See 2 more Smart Citations

Cristae formation is a mechanical buckling event controlled by the inner membrane lipidome

Venkatraman

Lee

García

et al. 2023

Preprint

Self Cite

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“…This provides a route for calcium, the main second messenger system in signaling, to interact directly with the energy production in a frequency-dependent manner. The thermodynamic constraints of ATP production in the mitochondria are explored in [21].…”

Section: Introductionmentioning

confidence: 99%

Computational modeling of AMPK and mTOR crosstalk in glutamatergic synapse calcium signaling

Leung

Rangamani

2022

Preprint

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Neuronal energy consumption is vital for information processing and memory formation in dendritic spines. The brain consists of just 2% of the human body's mass, but consumes almost 20% of the body's energy budget. Most of this energy is attributed to active transport in ion signaling, with calcium being the canonical second messenger of neuronal transmission. Here, we develop a model of synaptic signaling resulting in the activation of two protein kinases critical in metabolic regulation and cell fate, AMP-Activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) and investigate the effect of glutamate stimulus frequency on their dynamics. Our model predicts that higher frequencies of glutamate stimulus perturb AMPK and mTOR oscillations at higher magnitudes. This dynamic difference in AMPK and mTOR activation trajectories potentially differentiates high frequency stimulus bursts from basal neuronal signaling leading to a downstream change in synaptic plasticity. Further, we also investigate the crosstalk between insulin receptor and calcium signaling on AMPK and mTOR activation and predict that the pathways demonstrate multistability dependent on strength of insulin signaling and metabolic consumption rate. Our predictions have implications for improving our understanding of neuronal metabolism, synaptic pruning,and synaptic plasticity.

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Computational modeling of AMPK and mTOR crosstalk in glutamatergic synapse calcium signaling

Leung

Rangamani

2023

npj Syst Biol Appl

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Neuronal energy consumption is vital for information processing and memory formation in synapses. The brain consists of just 2% of the human body’s mass, but consumes almost 20% of the body’s energy budget. Most of this energy is attributed to active transport in ion signaling, with calcium being the canonical second messenger of synaptic transmission. Here, we develop a computational model of synaptic signaling resulting in the activation of two protein kinases critical in metabolic regulation and cell fate, AMP-Activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) and investigate the effect of glutamate stimulus frequency on their dynamics. Our model predicts that frequencies of glutamate stimulus over 10 Hz perturb AMPK and mTOR oscillations at higher magnitudes by up to 36% and change the area under curve (AUC) by 5%. This dynamic difference in AMPK and mTOR activation trajectories potentially differentiates high frequency stimulus bursts from basal neuronal signaling leading to a downstream change in synaptic plasticity. Further, we also investigate the crosstalk between insulin receptor and calcium signaling on AMPK and mTOR activation and predict that the pathways demonstrate multistability dependent on strength of insulin signaling and metabolic consumption rate. Our predictions have implications for improving our understanding of neuronal metabolism, synaptic pruning, and synaptic plasticity.

show abstract

Mitochondria morphology governs ATP production rate

Cited by 3 publications

References 56 publications

Cristae formation is a mechanical buckling event controlled by the inner membrane lipidome

Cristae formation is a mechanical buckling event controlled by the inner membrane lipidome

Computational modeling of AMPK and mTOR crosstalk in glutamatergic synapse calcium signaling

Computational modeling of AMPK and mTOR crosstalk in glutamatergic synapse calcium signaling

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