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  1. Article ; Online: Prescription drugs and mitochondrial metabolism.

    Schmidt, Cameron A

    Bioscience reports

    2022  Volume 42, Issue 4

    Abstract: Mitochondria are central to the physiology and survival of nearly all eukaryotic cells and house diverse metabolic processes including oxidative phosphorylation, reactive oxygen species buffering, metabolite synthesis/exchange, and Ca2+ sequestration. ... ...

    Abstract Mitochondria are central to the physiology and survival of nearly all eukaryotic cells and house diverse metabolic processes including oxidative phosphorylation, reactive oxygen species buffering, metabolite synthesis/exchange, and Ca2+ sequestration. Mitochondria are phenotypically heterogeneous and this variation is essential to the complexity of physiological function among cells, tissues, and organ systems. As a consequence of mitochondrial integration with so many physiological processes, small molecules that modulate mitochondrial metabolism induce complex systemic effects. In the case of many commonly prescribed drugs, these interactions may contribute to drug therapeutic mechanisms, induce adverse drug reactions, or both. The purpose of this article is to review historical and recent advances in the understanding of the effects of prescription drugs on mitochondrial metabolism. Specific 'modes' of xenobiotic-mitochondria interactions are discussed to provide a set of qualitative models that aid in conceptualizing how the mitochondrial energy transduction system may be affected. Findings of recent in vitro high-throughput screening studies are reviewed, and a few candidate drug classes are chosen for additional brief discussion (i.e. antihyperglycemics, antidepressants, antibiotics, and antihyperlipidemics). Finally, recent improvements in pharmacokinetics models that aid in quantifying systemic effects of drug-mitochondria interactions are briefly considered.
    MeSH term(s) Energy Metabolism ; Mitochondria/metabolism ; Oxidative Phosphorylation ; Prescription Drugs/metabolism ; Prescription Drugs/pharmacology ; Reactive Oxygen Species/metabolism
    Chemical Substances Prescription Drugs ; Reactive Oxygen Species
    Language English
    Publishing date 2022-03-22
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 764946-0
    ISSN 1573-4935 ; 0144-8463
    ISSN (online) 1573-4935
    ISSN 0144-8463
    DOI 10.1042/BSR20211813
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: "A Low-Cost Microfluidics System for Light Microscopy Experiments".

    Harrison, Logan M / Brisard, Benjamin M / Cashwell, Kylie D / Mulkey, Aaron L / Schmidt, Cameron A

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Microfluidics devices are powerful tools for studying dynamic processes in live cells, especially when used in conjunction with light microscopy. There are many applications of microfluidics devices including recording dynamic cellular responses to small ...

    Abstract Microfluidics devices are powerful tools for studying dynamic processes in live cells, especially when used in conjunction with light microscopy. There are many applications of microfluidics devices including recording dynamic cellular responses to small molecules or other chemical conditions in perfused media, monitoring cell migration in constrained spaces, or collecting media perfusate for the study of secreted compounds in response to experimental inputs/manipulations. Here we describe a configurable low-cost (channel-based) microfluidics platform for live-cell microscopy, intended to be useful for experiments that require more precision/flexibility than simple rubber spacers, but less precision than molded elastomer-based platforms. The materials are widely commercially available, low-cost, and device assembly takes only minutes.
    Language English
    Publishing date 2024-04-30
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.04.29.591694
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: From OCR and ECAR to energy: Perspectives on the design and interpretation of bioenergetics studies.

    Schmidt, Cameron A / Fisher-Wellman, Kelsey H / Neufer, P Darrell

    The Journal of biological chemistry

    2021  Volume 297, Issue 4, Page(s) 101140

    Abstract: Biological energy transduction underlies all physiological phenomena in cells. The metabolic systems that support energy transduction have been of great interest due to their association with numerous pathologies including diabetes, cancer, rare genetic ... ...

    Abstract Biological energy transduction underlies all physiological phenomena in cells. The metabolic systems that support energy transduction have been of great interest due to their association with numerous pathologies including diabetes, cancer, rare genetic diseases, and aberrant cell death. Commercially available bioenergetics technologies (e.g., extracellular flux analysis, high-resolution respirometry, fluorescent dye kits, etc.) have made practical assessment of metabolic parameters widely accessible. This has facilitated an explosion in the number of studies exploring, in particular, the biological implications of oxygen consumption rate (OCR) and substrate level phosphorylation via glycolysis (i.e., via extracellular acidification rate (ECAR)). Though these technologies have demonstrated substantial utility and broad applicability to cell biology research, they are also susceptible to historical assumptions, experimental limitations, and other caveats that have led to premature and/or erroneous interpretations. This review enumerates various important considerations for designing and interpreting cellular and mitochondrial bioenergetics experiments, some common challenges and pitfalls in data interpretation, and some potential "next steps" to be taken that can address these highlighted challenges.
    MeSH term(s) Diabetes Mellitus/metabolism ; Genetic Diseases, Inborn/metabolism ; Glycolysis ; Humans ; Mitochondria/metabolism ; Models, Biological ; Neoplasms/metabolism ; Oxidative Phosphorylation ; Oxygen Consumption
    Language English
    Publishing date 2021-08-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2021.101140
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Pyruvate modulation of redox potential controls mouse sperm motility.

    Schmidt, Cameron A / Hale, Benjamin J / Bhowmick, Debajit / Miller, William J / Neufer, P Darrell / Geyer, Christopher B

    Developmental cell

    2023  Volume 59, Issue 1, Page(s) 79–90.e6

    Abstract: Sperm gain fertilization competence in the female reproductive tract through a series of biochemical changes and a requisite switch from linear progressive to hyperactive motility. Despite being essential for fertilization, regulation of sperm energy ... ...

    Abstract Sperm gain fertilization competence in the female reproductive tract through a series of biochemical changes and a requisite switch from linear progressive to hyperactive motility. Despite being essential for fertilization, regulation of sperm energy transduction is poorly understood. This knowledge gap confounds interpretation of interspecies variation and limits progress in optimizing sperm selection for assisted reproduction. Here, we developed a model of mouse sperm bioenergetics using metabolic phenotyping data, quantitative microscopy, and spectral flow cytometry. The results define a mechanism of motility regulation by microenvironmental pyruvate. Rather than being consumed as a mitochondrial fuel source, pyruvate stimulates hyperactivation by repressing lactate oxidation and activating glycolysis in the flagellum through provision of nicotinamide adenine dinucleotide (NAD)
    MeSH term(s) Male ; Female ; Animals ; Mice ; Sperm Motility ; Pyruvic Acid/metabolism ; Semen/metabolism ; Energy Metabolism/physiology ; Spermatozoa/metabolism ; Oxidation-Reduction
    Chemical Substances Pyruvic Acid (8558G7RUTR)
    Language English
    Publishing date 2023-12-14
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2054967-2
    ISSN 1878-1551 ; 1534-5807
    ISSN (online) 1878-1551
    ISSN 1534-5807
    DOI 10.1016/j.devcel.2023.11.011
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Reply to Figueira et al.: Can NAD(P)

    Smith, Cody D / Schmidt, Cameron A / Fisher-Wellman, Kelsey H / Neufer, P Darrell

    The Journal of biological chemistry

    2021  Volume 296, Page(s) 100378

    MeSH term(s) Energy Metabolism ; Hydrogen Peroxide ; Mitochondria/metabolism ; NAD/metabolism ; NADP Transhydrogenase, AB-Specific/metabolism
    Chemical Substances NAD (0U46U6E8UK) ; Hydrogen Peroxide (BBX060AN9V) ; NADP Transhydrogenase, AB-Specific (EC 1.6.1.2)
    Language English
    Publishing date 2021-03-15
    Publishing country United States
    Document type Letter ; Comment
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2021.100378
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Flux through mitochondrial redox circuits linked to nicotinamide nucleotide transhydrogenase generates counterbalance changes in energy expenditure.

    Smith, Cody D / Schmidt, Cameron A / Lin, Chien-Te / Fisher-Wellman, Kelsey H / Neufer, P Darrell

    The Journal of biological chemistry

    2020  Volume 295, Issue 48, Page(s) 16207–16216

    Abstract: Compensatory changes in energy expenditure occur in response to positive and negative energy balance, but the underlying mechanism remains unclear. Under low energy demand, the mitochondrial electron transport system is particularly sensitive to added ... ...

    Abstract Compensatory changes in energy expenditure occur in response to positive and negative energy balance, but the underlying mechanism remains unclear. Under low energy demand, the mitochondrial electron transport system is particularly sensitive to added energy supply (
    MeSH term(s) Adenosine Diphosphate/metabolism ; Animals ; Energy Metabolism ; Hydrogen Peroxide/metabolism ; Male ; Mice ; Mitochondria, Muscle/enzymology ; Mitochondrial Proteins/metabolism ; NADP Transhydrogenase, AB-Specific/metabolism ; Oxidation-Reduction ; Oxygen Consumption
    Chemical Substances Mitochondrial Proteins ; Adenosine Diphosphate (61D2G4IYVH) ; Hydrogen Peroxide (BBX060AN9V) ; NADP Transhydrogenase, AB-Specific (EC 1.6.1.2) ; Nnt protein, mouse (EC 1.6.1.2)
    Keywords covid19
    Language English
    Publishing date 2020-08-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.RA120.013899
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Muscle progenitor cells are required for skeletal muscle regeneration and prevention of adipogenesis after limb ischemia.

    Abbas, Hasan / Olivere, Lindsey A / Padgett, Michael E / Schmidt, Cameron A / Gilmore, Brian F / McCord, Timothy J / Southerland, Kevin W / McClung, Joseph M / Kontos, Christopher D

    Frontiers in cardiovascular medicine

    2023  Volume 10, Page(s) 1118738

    Abstract: Skeletal muscle injury in peripheral artery disease (PAD) has been attributed to vascular insufficiency, however evidence has demonstrated that muscle cell responses play a role in determining outcomes in limb ischemia. Here, we demonstrate that genetic ... ...

    Abstract Skeletal muscle injury in peripheral artery disease (PAD) has been attributed to vascular insufficiency, however evidence has demonstrated that muscle cell responses play a role in determining outcomes in limb ischemia. Here, we demonstrate that genetic ablation of Pax7
    Language English
    Publishing date 2023-03-02
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2781496-8
    ISSN 2297-055X
    ISSN 2297-055X
    DOI 10.3389/fcvm.2023.1118738
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Mitochondria inside acute myeloid leukemia cells hydrolyze ATP to resist chemotherapy.

    Hagen, James T / Montgomery, Mclane M / Aruleba, Raphael T / Chrest, Brett R / Green, Thomas D / Kassai, Miki / Zeczycki, Tonya N / Schmidt, Cameron A / Bhowmick, Debajit / Tan, Su-Fern / Feith, David J / Chalfant, Charles E / Loughran, Thomas P / Liles, Darla / Minden, Mark D / Schimmer, Aaron D / Cabot, Myles C / Mclung, Joseph M / Fisher-Wellman, Kelsey H

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Despite early optimism, therapeutics targeting oxidative phosphorylation (OxPhos) have faced clinical setbacks, stemming from their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism ... ...

    Abstract Despite early optimism, therapeutics targeting oxidative phosphorylation (OxPhos) have faced clinical setbacks, stemming from their inability to distinguish healthy from cancerous mitochondria. Herein, we describe an actionable bioenergetic mechanism unique to cancerous mitochondria inside acute myeloid leukemia (AML) cells. Unlike healthy cells which couple respiration to the synthesis of ATP, AML mitochondria were discovered to support inner membrane polarization by consuming ATP. Because matrix ATP consumption allows cells to survive bioenergetic stress, we hypothesized that AML cells may resist cell death induced by OxPhos damaging chemotherapy by reversing the ATP synthase reaction. In support of this, targeted inhibition of BCL-2 with venetoclax abolished OxPhos flux without impacting mitochondrial membrane potential. In surviving AML cells, sustained polarization of the mitochondrial inner membrane was dependent on matrix ATP consumption. Mitochondrial ATP consumption was further enhanced in AML cells made refractory to venetoclax, consequential to downregulations in both the proton-pumping respiratory complexes, as well as the endogenous F
    Language English
    Publishing date 2024-04-15
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.04.12.589110
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: TIGAR deficiency enhances skeletal muscle thermogenesis by increasing neuromuscular junction cholinergic signaling.

    Tang, Yan / Zong, Haihong / Kwon, Hyokjoon / Qiu, Yunping / Pessin, Jacob B / Wu, Licheng / Buddo, Katherine A / Boykov, Ilya / Schmidt, Cameron A / Lin, Chien-Te / Neufer, P Darrell / Schwartz, Gary J / Kurland, Irwin J / Pessin, Jeffrey E

    eLife

    2022  Volume 11

    Abstract: Cholinergic and sympathetic counter-regulatory networks control numerous physiological functions, including learning/memory/cognition, stress responsiveness, blood pressure, heart rate, and energy balance. As neurons primarily utilize glucose as their ... ...

    Abstract Cholinergic and sympathetic counter-regulatory networks control numerous physiological functions, including learning/memory/cognition, stress responsiveness, blood pressure, heart rate, and energy balance. As neurons primarily utilize glucose as their primary metabolic energy source, we generated mice with increased glycolysis in cholinergic neurons by specific deletion of the fructose-2,6-phosphatase protein TIGAR. Steady-state and stable isotope flux analyses demonstrated increased rates of glycolysis, acetyl-CoA production, acetylcholine levels, and density of neuromuscular synaptic junction clusters with enhanced acetylcholine release. The increase in cholinergic signaling reduced blood pressure and heart rate with a remarkable resistance to cold-induced hypothermia. These data directly demonstrate that increased cholinergic signaling through the modulation of glycolysis has several metabolic benefits particularly to increase energy expenditure and heat production upon cold exposure.
    MeSH term(s) Acetylcholine/metabolism ; Animals ; Apoptosis Regulatory Proteins/metabolism ; Cholinergic Agents/metabolism ; Mice ; Muscle, Skeletal/metabolism ; Neuromuscular Junction/physiology ; Phosphoric Monoester Hydrolases/metabolism ; Thermogenesis
    Chemical Substances Apoptosis Regulatory Proteins ; Cholinergic Agents ; Phosphoric Monoester Hydrolases (EC 3.1.3.2) ; TIGAR protein, mouse (EC 3.1.3.2) ; Acetylcholine (N9YNS0M02X)
    Language English
    Publishing date 2022-03-07
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.73360
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article: Flux through mitochondrial redox circuits linked to nicotinamide nucleotide transhydrogenase generates counterbalance changes in energy expenditure

    Smith, Cody D / Schmidt, Cameron A / Lin, Chien-Te / Fisher-Wellman, Kelsey H / Neufer, P Darrell

    J. biol. chem

    Abstract: Compensatory changes in energy expenditure occur in response to positive and negative energy balance, but the underlying mechanism remains unclear. Under low energy demand, the mitochondrial electron transport system (ETS) is particularly sensitive to ... ...

    Abstract Compensatory changes in energy expenditure occur in response to positive and negative energy balance, but the underlying mechanism remains unclear. Under low energy demand, the mitochondrial electron transport system (ETS) is particularly sensitive to added energy supply (i.e., reductive stress) which exponentially increases the rate of H2O2 (JH2O2) production. H2O2 is reduced to H2O by electrons supplied by NADPH. NADP+ is reduced back to NADPH by activation of mitochondrial membrane potential-dependent nicotinamide nucleotide transhydrogenase (NNT). The coupling of reductive stress-induced JH2O2 production to NNT-linked redox buffering circuits provides a potential means of integrating energy balance with energy expenditure. To test this hypothesis, energy supply was manipulated by varying flux rate through ß-oxidation in muscle mitochondria minus/plus pharmacological or genetic inhibition of redox buffering circuits. Here we show during both non-ADP and low-ADP stimulated respiration that accelerating flux through ß-oxidation generates a corresponding increase in mitochondrial JH2O2 production, that the majority (∼70-80%) of H2O2 produced is reduced to H2O by electrons drawn from redox buffering circuits supplied by NADPH, and that the rate of electron flux through redox buffering circuits is directly linked to changes in oxygen consumption mediated by NNT. These findings provide evidence that redox reactions within ß-oxidation and the ETS serve as a barometer of substrate flux relative to demand, continuously adjusting JH2O2 production and, in turn, the rate at which energy is expended via NNT-mediated proton conductance. This variable flux through redox circuits provides a potential compensatory mechanism for fine-tuning energy expenditure to energy balance in real-time.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #32747443
    Database COVID19

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