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1. Computational Modeling of Substrate-Dependent Mitochondrial Respiration and Bioenergetics in the Heart and Kidney Cortex and Outer Medulla

   https://doi.org/10.1093/function/zqad038  

   Sadri, Shima; Zhang, Xiao; Audi, Said_H; Cowley Jr, Allen_W; Dash, Ranjan_K (July 2023, Function)

   Abstract Integrated computational modeling provides a mechanistic and quantitative framework to characterize alterations in mitochondrial respiration and bioenergetics in response to different metabolic substrates in-silico. These alterations play critical roles in the pathogenesis of diseases affecting metabolically active organs such as heart and kidney. Therefore, the present study aimed to develop and validate thermodynamically constrained integrated computational models of mitochondrial respiration and bioenergetics in the heart and kidney cortex and outer medulla (OM). The models incorporated the kinetics of major biochemical reactions and transport processes as well as regulatory mechanisms in the mitochondria of these tissues. Intrinsic model parameters such as Michaelis–Menten constants were fixed at previously estimated values, while extrinsic model parameters such as maximal reaction and transport velocities were estimated separately for each tissue. This was achieved by fitting the model solutions to our recently published respirometry data measured in isolated rat heart and kidney cortex and OM mitochondria utilizing various NADH- and FADH2-linked metabolic substrates. The models were validated by predicting additional respirometry and bioenergetics data, which were not used for estimating the extrinsic model parameters. The models were able to predict tissue-specific and substrate-dependent mitochondrial emergent metabolic system properties such as redox states, enzyme and transporter fluxes, metabolite concentrations, membrane potential, and respiratory control index under diverse physiological and pathological conditions. The models were also able to quantitatively characterize differential regulations of NADH- and FADH2-linked metabolic pathways, which contribute differently toward regulations of oxidative phosphorylation and ATP synthesis in the heart and kidney cortex and OM mitochondria. 

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2. The Role of Swelling in the Regulation of OPA1-Mediated Mitochondrial Function in the Heart In Vitro

   https://doi.org/10.3390/cells12162017  

   Chapa-Dubocq, Xavier R.; Rodríguez-Graciani, Keishla M.; García-Báez, Jorge; Vadovsky, Alyssa; Bazil, Jason N.; Javadov, Sabzali (August 2023, Cells)

   Optic atrophy-1 (OPA1) plays a crucial role in the regulation of mitochondria fusion and participates in maintaining the structural integrity of mitochondrial cristae. Here we elucidate the role of OPA1 cleavage induced by calcium swelling in the presence of Myls22 (an OPA1 GTPase activity inhibitor) and TPEN (an OMA1 inhibitor). The rate of ADP-stimulated respiration was found diminished by both inhibitors, and they did not prevent Ca2+-induced mitochondrial respiratory dysfunction, membrane depolarization, or swelling. L-OPA1 cleavage was stimulated at state 3 respiration; therefore, our data suggest that L-OPA1 cleavage produces S-OPA1 to maintain mitochondrial bioenergetics in response to stress. 

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3. Gut bacterial lactate stimulates lung epithelial mitochondria and exacerbates acute lung injury

   https://doi.org/10.1101/2025.03.24.645052  

   Upadhyay, Vaibhav; Ortega, Edwin F; Ramirez_Hernandez, Luis A; Alexander, Margaret; Kaur, Gagandeep; Trepka, Kai; Rock, Rachel R; Shima, Rafaella T; Cheshire, W Colby; Alipanah-Lechner, Narges; et al (March 2025, bioRxiv)

   ABSTRACT Acute respiratory distress syndrome (ARDS) is an often fatal critical illness where lung epithelial injury leads to intrapulmonary fluid accumulation. ARDS became widespread during the COVID-19 pandemic, motivating a renewed effort to understand the complex etiology of this disease. Rigorous prior work has implicated lung endothelial and epithelial injury in response to an insult such as bacterial infection; however, the impact of microorganisms found in other organs on ARDS remains unclear. Here, we use a combination of gnotobiotic mice, cell culture experiments, and re-analyses of a large metabolomics dataset from ARDS patients to reveal that gut bacteria impact lung cellular respiration by releasing metabolites that alter mitochondrial activity in lung epithelium. Colonization of germ-free mice with a complex gut microbiota stimulated lung mitochondrial gene expression. A single human gut bacterial species,Bifidobacterium adolescentis,was sufficient to replicate this effect, leading to a significant increase in mitochondrial membrane potential in lung epithelial cells. We then used genome sequencing and mass spectrometry to confirm thatB. adolescentisproducesL-lactate, which was sufficient to increase mitochondrial activity in lung epithelial cells. Finally, we found that serum lactate was significantly associated with disease severity in patients with ARDS from the Early Assessment of Renal and Lung Injury (EARLI) cohort. Together, these results emphasize the importance of more broadly characterizing the microbial etiology of ARDS and other lung diseases given the ability of gut bacterial metabolites to remotely control lung cellular respiration. Our discovery of a single bacteria-metabolite pair provides aproof-of-conceptfor systematically testing other microbial metabolites and a mechanistic biomarker that could be pursued in future clinical studies. Furthermore, our work adds to the growing literature linking the microbiome to mitochondrial function, raising intriguing questions as to the bidirectional communication between our endo- and ecto-symbionts. 

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4. The Blood-Brain Barrier and Bioenergetics in Stroke

   https://doi.org/10.4172/2314-7326.1000298  

   Emily Hone, Sajad Sarvari (July 2021, Journal of Neuroinfectious Diseases)

   null (Ed.)

   Stroke is an overwhelming neurological disease with very limited treatment options. As blood-brain barrier (BBB) integrity is well-implicated in the prevention of brain injury, its regulation may prove beneficial for stroke patients. BBB cerebro-vascular endothelial cells primarily utilize mitochondria as their energy-producing source, and mitochondrial function has revealed importance in outcomes for tissue post-stroke. In this review, bioenergetics in relation to BBB permeability in stroke is discussed. Moreover, what causes mitochondrial dysfunction following stroke is explored. 

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5. Full-lung simulations of mechanically ventilated lungs incorporating recruitment/derecruitment dynamics

   https://doi.org/10.3389/fnetp.2023.1257710  

   Ma, Haoran; Fujioka, Hideki; Halpern, David; Bates, Jason H.; Gaver, Donald P. (November 2023, Frontiers in Network Physiology)

   Egidio Paolo Beretta (Ed.)

   This study developed and investigated a comprehensive multiscale computational model of a mechanically ventilated ARDS lung to elucidate the underlying mechanisms contributing to the development or prevention of VILI. This model is built upon a healthy lung model that incorporates realistic airway and alveolar geometry, tissue distensibility, and surfactant dynamics. Key features of the ARDS model include recruitment and derecruitment (RD) dynamics, alveolar tissue viscoelasticity, and surfactant deficiency. This model successfully reproduces realistic pressure-volume (PV) behavior, dynamic surface tension, and time-dependent descriptions of RD events as a function of the ventilation scenario. Simulations of Time-Controlled Adaptive Ventilation (TCAV) modes, with short and long durations of exhalation (T_Low^-andT_Low⁺, respectively), reveal a higher incidence of RD forT_Low⁺despite reduced surface tensions due to interfacial compression. This finding aligns with experimental evidence emphasizing the critical role of timing in protective ventilation strategies. Quantitative analysis of energy dissipation indicates that while alveolar recruitment contributes only a small fraction of total energy dissipation, its spatial concentration and brief duration may significantly contribute to VILI progression due to its focal nature and higher intensity. Leveraging the computational framework, the model may be extended to facilitate the development of personalized protective ventilation strategies to enhance patient outcomes. As such, this computational modeling approach offers valuable insights into the complex dynamics of VILI that may guide the optimization of ventilation strategies in ARDS management. 

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