CoChat
Sign Up
Cited by 286Metabolism, Diabetes, and CancerMitochondrial Function and PathologySirtuins and Resveratrol in Medicine

AMPK, Mitochondrial Function, and Cardiovascular Disease

Open access
Wu, Shengnan, Zou, Ming-Hui·2020·International Journal of Molecular Sciences
DOI 10.3390/ijms21144987PMC PMC7404275
Open this paper in CoChat — free accountOpen PDF

Abstract

Adenosine monophosphate-activated protein kinase (AMPK) is in charge of numerous catabolic and anabolic signaling pathways to sustain appropriate intracellular adenosine triphosphate levels in response to energetic and/or cellular stress. In addition to its conventional roles as an intracellular energy switch or fuel gauge, emerging research has shown that AMPK is also a redox sensor and modulator, playing pivotal roles in maintaining cardiovascular processes and inhibiting disease progression. Pharmacological reagents, including statins, metformin, berberine, polyphenol, and resveratrol, all of which are widely used therapeutics for cardiovascular disorders, appear to deliver their protective/therapeutic effects partially via AMPK signaling modulation. The functions of AMPK during health and disease are far from clear. Accumulating studies have demonstrated crosstalk between AMPK and mitochondria, such as AMPK regulation of mitochondrial homeostasis and mitochondrial dysfunction causing abnormal AMPK activity. In this review, we begin with the description of AMPK structure and regulation, and then focus on the recent advances toward understanding how mitochondrial dysfunction controls AMPK and how AMPK, as a central mediator of the cellular response to energetic stress, maintains mitochondrial homeostasis. Finally, we systemically review how dysfunctional AMPK contributes to the initiation and progression of cardiovascular diseases via the impact on mitochondrial function.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that AMPK is both a redox sensor/modulator and a central regulator of mitochondrial homeostasis, with bidirectional crosstalk: mitochondrial dysfunction can alter AMPK activity, while AMPK controls mitochondrial biogenesis, dynamics, mitophagy, and Ca²⁺ handling. Dysregulated AMPK–mitochondria signaling contributes to cardiovascular disease, and drugs such as metformin, berberine, statins, polyphenols, and resveratrol may act partly through AMPK.

Key findings

  • AMPK is a heterotrimeric complex of α, β, and γ subunits; all isoform combinations produce 12 different AMPK complexes. It is activated by AMP/ADP and inhibited by ATP, with LKB1 and CAMKK2 as major upstream kinases; Thr172 phosphorylation increases AMPK activity about 100-fold, while allosteric regulation changes activity up to tenfold in mammalian cells and about twofold in recombinant bacterially produced AMPK.
  • AMPK functions as a redox sensor and antioxidant modulator: ROS/RNS can activate AMPK via energy stress and/or LKB1–CaMKK signaling, while activated AMPK suppresses mitochondrial and NOX-derived ROS and upregulates antioxidant genes including CAT, SOD1, SOD2, and UCP2, often through PGC1α.
  • AMPK regulates mitochondrial homeostasis by promoting mitochondrial biogenesis via PGC1α, controlling mitochondrial dynamics through MFF phosphorylation at Ser155/Ser173 and DRP1, regulating mitophagy through ULK1 and PINK1–PARKIN signaling, and modulating mitochondrial Ca²⁺ influx through MCU.
  • In cardiovascular disease, AMPK is generally protective across atherosclerosis, ischemia, ischemia/reperfusion injury, vascular calcification, neointimal hyperplasia, cardiac hypertrophy, diabetes, inflammation, and obesity; the review notes that reperfusion failure occurs in approximately 30% of patients with acute myocardial infarction and that ischemic heart disease accounted for 15.96% of total global deaths in 2017.

Methods

  • Not stated in the paper; the text is a narrative review that synthesizes cited literature rather than presenting original experimental data.
  • The review covers AMPK structure and regulation, redox regulation of AMPK, mitochondrial control of AMPK, AMPK regulation of mitochondrial homeostasis, and AMPK–mitochondria signaling in cardiovascular and cardio-metabolic diseases.
  • Main analysis is qualitative synthesis of mechanistic studies across cell, animal, and some human contexts; no systematic search strategy, inclusion criteria, or meta-analysis is described.

Limitations

  • Stated: the authors note that the functions of AMPK during health and disease are “far from clear” and that the interplay within the AMPK–mitochondrial axis during cardiovascular disease initiation and progression is poorly investigated.
  • Stated: limited evidence has focused on mitochondrial dynamics, mitochondrial biogenesis, and mitophagy, and the structural and functional changes to mitochondria under disease conditions remain “far beyond our current knowledge.”
  • Evident from the text: as a narrative review, it does not provide primary data, systematic evidence grading, or quantitative synthesis; many mechanistic conclusions are drawn from preclinical cell and animal models, with clinical evidence cited more selectively.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/ijms21144987

Cites

275 of 275 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 250 cited sources checked · 0 supported · 0 flagged

  • Interpretationnone given

    Pharmacological reagents including statins, metformin, berberine, polyphenol, and resveratrol appear to deliver their protective/therapeutic effects partially via AMPK signaling modulation.

    “Pharmacological reagents, including statins, metformin, berberine, polyphenol, and resveratrol, all of which are widely used therapeutics for cardiovascular disorders, appear to deliver their protective/therapeutic effects partially via AMPK signaling modulation.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Binding of AMP, and to a lesser degree ADP, to the γ-subunit stimulates AMPK activity via three mechanisms.

    “Binding of AMP, and to a lesser degree ADP, to the γ-subunit stimulates AMPK activity via three mechanisms [27,28,29].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [27] Hardie, 2011, AMP-activated protein kinase: Also regulated by ADP?, Trends Biochem. Sci. source

      Not checked in the free run.

    • cites [28] Gowans, 2013, AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation, Cell Metab. source

      Not checked in the free run.

    • cites [29] Ross, 2016, Differential regulation by AMP and ADP of AMPK complexes containing different gamma subunit isoforms, Biochem. J. source

      Not checked in the free run.

  • Premisecitation

    AMP protects Thr172 against dephosphorylation by phosphatases.

    “Second, AMP protects Thr172 against dephosphorylation by phosphatases [28,35,36,37].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [28] Gowans, 2013, AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation, Cell Metab. source

      Not checked in the free run.

    • cites [35] Xiao, 2011, Structure of mammalian AMPK and its regulation by ADP, Nature source

      Not checked in the free run.

    • cites [36] Neumann, 2010, The PP1-R6 protein phosphatase holoenzyme is involved in the glucose-induced dephosphorylation and inactivation of AMP-activated protein kinase, a key regulator of insulin secretion, in MIN6 beta cells, FASEB J.

      Not checked in the free run.

    • cites [37] Joseph, 2015, Inhibition of AMP kinase by the protein phosphatase 2a heterotrimer, PP2APpp2r2d, J. Biol. Chem. source

      Not checked in the free run.

  • Premisecitation

    Once activated, AMPK redirects metabolism toward increased catabolism or decreased anabolism through phosphorylation of key proteins across multiple pathways, including protein synthesis, lipid homeostasis, glucose metabolism, and mitochondrial homeostasis.

    “Once activated, AMPK redirects metabolism toward increased catabolism or decreased anabolism through the phosphorylation of key proteins across multiple pathways, including protein synthesis (e.g., mammalian target of rapamycin complex (1) [2,3], lipid homeostasis (e.g., acetyl coenzyme A carboxylase, ACC) [4,5], glucose metabolism (e.g., phosphofructokinase (2) [6], and mitochondrial homeostasis”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [2] Gwinn, 2008, AMPK phosphorylation of raptor mediates a metabolic checkpoint, Mol. Cell source

      Not checked in the free run.

    • cites [3] Inoki, 2003, TSC2 mediates cellular energy response to control cell growth and survival, Cell source

      Not checked in the free run.

    • cites [4] Carling, 1987, A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis, FEBS Lett. source

      Not checked in the free run.

    • cites [5] Munday, 1988, Identification by amino acid sequencing of three major regulatory phosphorylation sites on rat acetyl-CoA carboxylase, Eur. J. Biochem. source

      Not checked in the free run.

    • cites [7] Jager, 2007, AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

  • Premisenone given

    AMPK is activated by energy stress and/or cellular stress in response to increased ATP consumption or decreased ATP production, sensed as low ratios of ATP-to-AMP/ADP.

    “AMPK is activated by energy stress and/or cellular stress in response to increased ATP consumption (e.g., exercise, cell proliferation, and anabolism) or decreased ATP production (e.g., low glucose levels, oxidative stress, and hypoxia), which are sensed as low ratios of ATP-to-AMP/ADP.”
    Quote in the paperSubstantial claim
  • May combine two claims. 71
  • Classified as probably not a substantial claim. 21

  • May combine two claims.

    Interpretationnone given

    AMPK is a redox sensor and modulator that plays pivotal roles in maintaining cardiovascular processes and inhibiting disease progression.

    “In addition to its conventional roles as an intracellular energy switch or fuel gauge, emerging research has shown that AMPK is also a redox sensor and modulator, playing pivotal roles in maintaining cardiovascular processes and inhibiting disease progression.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In humans, each AMPK subunit has multiple distinct isoforms encoded by different genes: α1 and α2 by PRKAA1 and PRKAA2; β1 and β2 by PRKAB1 and PRKAB2; γ1, γ2, and γ3 by PRKAG1, PRKAG2, and PRKAG3.

    “In humans, each subunit has multiple distinct isoforms encoded by different genes: the α-subunit has two isoforms, α1 and α2, encoded by gene PRKAA1 and PRKAA2, respectively [20]; the β-subunit has two isoforms, β1 and β2, encoded by gene PRKAB1 and PRKAB2, respectively [21]; and the γ-subunit has three isoforms, γ1, γ2, and γ3, encoded by gene PRKAG1, PRKAG2, and PRKAG3, respectively [22].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [20] Stapleton, 1996, Mammalian AMP-activated protein kinase subfamily, J. Biol. Chem. source

      Not checked in the free run.

    • cites [21] Thornton, 1998, Identification of a novel AMP-activated protein kinase beta subunit isoform that is highly expressed in skeletal muscle, J. Biol. Chem. source

      Not checked in the free run.

    • cites [22] Cheung, 2000, Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding, Biochem. J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation loop phosphorylation increases AMPK activity by about 100-fold, while allosteric regulation changes AMPK activity up to tenfold in mammalian cells and about twofold in recombinant, bacterially produced AMPK.

    “Activation loop phosphorylation increases AMPK activity by about 100-fold, while allosteric regulation changes AMPK activity up to tenfold in mammalian cells and about twofold in recombinant, bacterially produced AMPK [26,28,38,39].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [26] Xiao, 2007, Structural basis for AMP binding to mammalian AMP-activated protein kinase, Nature source

      Not checked in the free run.

    • cites [28] Gowans, 2013, AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation, Cell Metab. source

      Not checked in the free run.

    • cites [38] Sanders, 2007, Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family, J. Biol. Chem. source

      Not checked in the free run.

    • cites [39] Davies, 1995, 5’-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C alpha and native bovine protein phosphatase-2AC, FEBS Lett. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    ROS are free radicals and chemically reactive molecules derived from oxygen.

    “ROS are plenty of free radicals and chemically reactive molecules derived from oxygen molecule [41].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Alfadda, 2012, Reactive oxygen species in health and disease, J. Biomed. Biotechnol. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Accumulating studies have demonstrated crosstalk between AMPK and mitochondria, such as AMPK regulation of mitochondrial homeostasis and mitochondrial dysfunction causing abnormal AMPK activity.

    “Accumulating studies have demonstrated crosstalk between AMPK and mitochondria, such as AMPK regulation of mitochondrial homeostasis and mitochondrial dysfunction causing abnormal AMPK activity.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    All possible combinations of AMPK subunits produce 12 different AMPK complexes.

    “Each AMPK complex is comprised of an α-subunit, a β-subunit, and a γ-subunit, and all possible combinations produce 12 different AMPK complexes [23].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Ross, 2016, AMP-activated protein kinase: A cellular energy sensor that comes in 12 flavours, FEBS J. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The γ-subunit includes four tandem cystathionine β synthase motifs that allow AMPK to bind adenine nucleotides and react to changes in AMP, ADP, and ATP.

    “The γ-subunit allows AMPK to react to changes in the level of AMP, ADP, and ATP, as it includes four tandem cystathionine β synthase motifs that allow AMPK to bind adenine nucleotides [26].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Xiao, 2007, Structural basis for AMP binding to mammalian AMP-activated protein kinase, Nature source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Excessive production of ROS, usually termed oxidative stress, is caused by increased production and/or insufficient presence of endogenous antioxidants.

    “Excessive production of ROS, usually termed oxidative stress, are caused by increased production and/or insufficient presence of endogenous antioxidants [41].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Alfadda, 2012, Reactive oxygen species in health and disease, J. Biomed. Biotechnol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Most ROS are generated as byproducts of mitochondrial electron transportation from the reduction of molecular oxygen to produce superoxide.

    “Most ROS are generated as byproducts of mitochondrial electron transportation from the reduction of molecular oxygen to produce superoxide [41].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Alfadda, 2012, Reactive oxygen species in health and disease, J. Biomed. Biotechnol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Oxidative stress damages fats, DNA, and proteins in a cell, which can lead to diseases such as diabetes, cancer, neurodegenerative disease, and cardiovascular disease.

    “Oxidative stress is considered detrimental because of its damage to fats, deoxyribonucleic acid, and proteins in a cell, which can lead to numerous diseases such as diabetes, cancer, neurodegenerative disease, and cardiovascular disease (CVD) [41].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Alfadda, 2012, Reactive oxygen species in health and disease, J. Biomed. Biotechnol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    AMPK is a heterotrimeric complex composed of a catalytic α-subunit and β and γ regulatory subunits.

    “AMPK, a heterotrimeric complex, is composed of a catalytic α-subunit and beta (β) and gamma (γ) regulatory subunits [19].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Yan, Y., Zhou, X.E., Xu, H.E., and Melcher, K. (2018). Structure and physiological regulation of AMPK. Int. J. Mol. Sci., 19. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The β-subunit includes a carbohydrate-binding module that grants AMPK the ability to bind glycogen.

    “The β-subunit includes a carbohydrate-binding module that grants AMPK to bind to glycogen [25].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Hudson, 2003, A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias, Curr. Biol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Allosteric AMPK activation can occur in non-phosphorylated AMPK, with even higher fold activation than phosphorylated AMPK.

    “Lastly, allosteric AMPK activation can also occur in non-phosphorylated AMPK, with even higher fold activation than phosphorylated AMPK [40].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Willows, 2017, Phosphorylation of AMPK by upstream kinases is required for activity in mammalian cells, Biochem. J. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Double knockout of AMPKα1 and AMPKα2 in mice gives rise to embryonic lethality.

    “The α-subunit is essential, and a double knockout (KO) of AMPKα1 and AMPKα2 in mice gives rise to embryonic lethality [24].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Viollet, 2009, AMPK: Lessons from transgenic and knockout animals, Front. Biosci. (Landmark Ed.) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The α-subunit contains the kinase domain and a critical residue (Thr174 in α1 and Thr172 in α2) that is phosphorylated by upstream kinases.

    “The α-subunit contains the kinase domain and a critical residue (Thr174 in α1-subunit and Thr172 in α2-subunit, hereafter referred to as Thr172) that is phosphorylated by upstream kinases [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Hardie, 2012, AMPK: A nutrient and energy sensor that maintains energy homeostasis, Nat. Rev. Mol. Cell Biol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    LKB1 and CAMKK2 are the two main mammalian upstream molecules that phosphorylate AMPK.

    “Liver kinase B 1 (LKB1) [32] and calcium/calmodulin-dependent protein kinase kinase (CAMKK) 2 [33,34] can be employed as the two main mammalian upstream molecules that phosphorylate AMPK.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [32] Woods, 2003, LKB1 is the upstream kinase in the AMP-activated protein kinase cascade, Curr. Biol. source

      Not checked in the free run.

    • cites [33] Fujiwara, 2016, Differential AMP-activated Protein Kinase (AMPK) Recognition mechanism of Ca2+/calmodulin-dependent protein kinase kinase isoforms, J. Biol. Chem. source

      Not checked in the free run.

    • cites [34] Hawley, 2005, Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In H4IIEC3 cells, exogenous hydrogen peroxide transiently increased phosphor-AMPK by LKB1 signaling, while in HeLa cells it promoted AMPK phosphorylation by CaMKK signaling.

    “In H4IIEC3 cells, exogenous hydrogen peroxide transiently increased the level of phosphor-AMPK by LKB1 signaling, while exogenous hydrogen peroxide promoted AMPK phosphorylation in HeLa cells by CaMKK signaling [42].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Liangpunsakul, 2008, Effect of ethanol on hydrogen peroxide-induced AMPK phosphorylation, Am. J. Physiol. Gastrointest. Liver Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TPr agonist-activated AMPK is mediated by hydrogen peroxide, as overexpression of catalase abolished TPr agonist-induced AMPK activation.

    “TPr agonists-activated AMPK was mediated by hydrogen peroxide, as demonstrated by the results showing overexpression of catalase (CAT) abolished Tpr agonists-induced AMPK activation [61].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Zhang, 2008, Thromboxane receptor activates the AMP-activated protein kinase in vascular smooth muscle cells via hydrogen peroxide, Circ. Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Exogenous or glucose oxidase-generated hydrogen peroxide induced direct S-glutathionylation on the AMPKα subunit at Cys299 and Cys304, which contributes to AMPK activation.

    “Exogenous or glucose oxidase-generated hydrogen peroxide induced direct S-glutathionylation on the AMPKα subunit at Cys299 and Cys304, which contributes to AMPK activation [48].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Zmijewski, 2010, Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Decreased NO bioavailability occurs in response to lipid infiltration, oxidative stress, and inflammatory factors, which play a vital role in endothelial dysfunction.

    “Its decrease occurs in response to lipid infiltration, oxidative stress, and inflammatory factors, which play a vital role in endothelial dysfunction [153].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] Chen, 2018, Nitric oxide bioavailability dysfunction involves in atherosclerosis, Biomed. Pharmacother. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AMPK negatively regulates NOX by reducing its phosphorylation and preventing P47phox's translocation to membrane.

    “Additional evidence supporting AMPK protection against oxidative stress is that AMPK negatively regulates NOX by reducing its phosphorylation and preventing P47phox’s translocation to membrane [70,151].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [70] Wang, 2010, AMPKalpha2 deletion causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo: Role of 26S proteasomes, Circ. Res. source

      Not checked in the free run.

    • cites [151] McCarty, 2009, AMP-activated kinase may suppress NADPH oxidase activation in vascular tissues, Med. Hypotheses source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Suppression of oxidative stress blunted activation of the protein kinase B-cyclic AMP-responsive element binding protein-PGC1α pathway, which ameliorated mitochondrial dysfunction and apoptosis.

    “Moreover, the suppression of oxidative stress, in turn, blunted the activation of the protein kinase B-cyclic AMP-responsive element binding protein–PGC1α pathway, which ameliorated mitochondrial dysfunction and apoptosis [129].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [129] Ou, 2019, Fucoxanthin protects against oxLDL-induced endothelial damage via activating the AMPK-Akt-CREB-PGC1alpha pathway, Mol. Nutr. Food Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Some studies showed that ROS directly activated AMPK independent of changes in ADP, AMP, and ATP.

    “Alternatively, some studies showed that ROS directly activated AMPK independent of changes in ADP, AMP, and ATP.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    AMPK suppresses protein kinase C activity and prevents protein kinase C modulation of p47phox phosphorylation.

    “AMPK suppresses protein kinase C activity and prevents protein kinase C modulation of p47phox phosphorylation [152].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [152] Ou, 2013, Ginkgo biloba extract attenuates oxLDL-induced endothelial dysfunction via an AMPK-dependent mechanism, J. Appl. Physiol. (1985) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    ROS-induced energy stress strongly activates AMPK, which is likely the main mechanism of ROS-mediated AMPK activation.

    “It is well established that the ROS-induced energy stress strongly activates AMPK, which is likely the main mechanism of ROS-mediated AMPK activation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In NIH-3T3 cells, exogenous hydrogen peroxide transiently activated AMPK in a dose-dependent manner, associated with an increased AMP-to-ATP ratio.

    “Similarly, in NIH-3T3 cells, exogenous hydrogen peroxide transiently activated AMPK in a dose-dependent manner, which was associated with an increased AMP-to-ATP ratio [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Choi, 2001, The regulation of AMP-activated protein kinase by H(2)O(2), Biochem. Biophys. Res. Commun. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vasculature I/R injury alleviates the efficiency of reperfusion therapy and compromises the clinical benefits of patients with acute MI.

    “Vasculature I/R injury alleviates the efficiency of reperfusion therapy and compromises the clinical benefits of patients with acute MI [181].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [181] Ndrepepa, 2010, 5-year prognostic value of no-reflow phenomenon after percutaneous coronary intervention in patients with acute myocardial infarction, J. Am. Coll. Cardiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    With increasing mitochondria, the level of ROS is also increased as mitochondrial byproducts, which can result in oxidative damage of mitochondria.

    “However, with increasing mitochondria, the level of ROS is also increased as mitochondrial byproducts, which can result in oxidative damage of mitochondria [176].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [176] Fischer, 2012, Mitochondrial quality control: An integrated network of pathways, Trends Biochem. Sci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondria-targeted esculetin greatly alleviated angiotensin II-induced monocyte infiltration, atherosclerotic plaque formation, and serum pro-inflammatory cytokine production in apolipoprotein E KO mice.

    “Mitochondria-targeted esculetin, capable of scavenging mitochondrial ROS, greatly alleviated angiotensin II-induced monocyte infiltration, atherosclerotic plaque formation, and serum pro-inflammatory cytokine production in apolipoprotein E KO mice [131].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [131] Karnewar, 2016, Mitochondria-targeted esculetin alleviates mitochondrial dysfunction by AMPK-mediated nitric oxide and SIRT3 regulation in endothelial cells: Potential implications in atherosclerosis, Sci. Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During early reperfusion, treatment with metformin augmented I/R-induced AMPK activation and significantly increased eNOS phosphorylation at ser1177.

    “During early reperfusion, treatment with metformin augmented I/R-induced AMPK activation and significantly increased eNOS phosphorylation at ser1177 [183].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [183] Calvert, 2008, Acute metformin therapy confers cardioprotection against myocardial infarction via AMPK-eNOS-mediated signaling, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Apoptosis induces endothelial swelling, microvascular spasms, and capillary obstruction, which slows or even stops microcirculation blood flow following reperfusion.

    “The apoptosis induces endothelial swelling, microvascular spasms, and capillary obstruction, which slows or even stops microcirculation blood flow following reperfusion [179].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [179] Kloner, 1974, The “no-reflow” phenomenon after temporary coronary occlusion in the dog, J. Clin. Investig. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    AMPK participates in mitophagy regulation, which thereby provides a valuable therapeutic target for ischemic heart diseases.

    “These results suggest that AMPK participates in mitophagy regulation, which thereby provides a valuable therapeutic target for ischemic heart diseases.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Zhang, 2018, AMPK activation serves a critical role in mitochondria quality control via modulating mitophagy in the heart under chronic hypoxia, Int. J. Mol. Med.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tube formation in mouse arterial endothelial cells isolated from either AMPKα1−/− or AMPKα2−/− mice was significantly impaired, exhibiting oxidative stress and reduced expression of UCP2.

    “Similarly, in comparison with the WT cells, tube formation in mouse arterial endothelial cells isolated from either AMPKα1−/− or AMPKα2−/− mice was significantly impaired, exhibiting oxidative stress and reduced expression of UCP2.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] Xu, 2011, Impaired expression of uncoupling protein 2 causes defective postischemic angiogenesis in mice deficient in AMP-activated protein kinase alpha subunits, Arterioscler. Thromb. Vasc. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitophagy increased significantly in cardiomyocytes exposed to hypoxic conditions, which was accompanied by AMPK activation.

    “Mitophagy increased significantly in cardiomyocytes exposed to hypoxic conditions, which was accompanied by AMPK activation [133].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Zhang, 2018, AMPK activation serves a critical role in mitochondria quality control via modulating mitophagy in the heart under chronic hypoxia, Int. J. Mol. Med.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under chronic hypoxia, PGC1α is upregulated, resulting in a subsequent increase of mitochondrial biogenesis.

    “Under chronic hypoxia, PGC1α is upregulated, resulting in a subsequent increase of mitochondrial biogenesis [175].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [175] Zhu, 2010, Hypoxia induces PGC-1alpha expression and mitochondrial biogenesis in the myocardium of TOF patients, Cell Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment of cardiomyocytes with carvedilol augmented phosphorylation of AMPK and its downstream substrate ACC, and ameliorated hypoxia-induced impairment.

    “Treatment of cardiomyocytes with carvedilol augmented phosphorylation of AMPK and its downstream substrate ACC, and ameliorated hypoxia-induced impairment [182].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [182] Hu, 2019, The cardioprotective effects of carvedilol on ischemia and reperfusion injury by AMPK signaling pathway, Biomed. Pharmacother. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AMPK decreased apoptosis, improved post-ischemic recovery, and limited myocardial infarction.

    “Mechanically, AMPK increased glucose uptake and glucose transporter 4 translocation [171], decreased apoptosis, improved post-ischemic recovery, and limited myocardial infarction (MI) [172,173].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [172] Ma, 2010, Impaired macrophage migration inhibitory factor-AMP-activated protein kinase activation and ischemic recovery in the senescent heart, Circulation source

      Not checked in the free run.

    • cites [173] Russell, 2004, AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury, J. Clin. Investig. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When AMPK activation was blocked, mitophagy decreased as well, which subsequently gave rise to cardiomyocyte apoptosis.

    “Consistently, when AMPK activation was blocked, mitophagy decreased as well, which subsequently gave rise to cardiomyocyte apoptosis [133].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [133] Zhang, 2018, AMPK activation serves a critical role in mitochondria quality control via modulating mitophagy in the heart under chronic hypoxia, Int. J. Mol. Med.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    I/R injury causes myocardial damage and increases 30-day mortality rates.

    “I/R injury causes myocardial damage and increases 30-day mortality rates [180].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [180] Abbate, 2008, No-reflow: The next challenge in treatment of ST-elevation acute myocardial infarction, Eur. Heart J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AMPK increased glucose uptake and glucose transporter 4 translocation.

    “Mechanically, AMPK increased glucose uptake and glucose transporter 4 translocation [171], decreased apoptosis, improved post-ischemic recovery, and limited myocardial infarction (MI) [172,173].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [171] Miller, 2008, Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    I/R triggered a DRP1-dependent mitochondrial fragmentation, which subsequently led to oligomerization of voltage-dependent anion channel 1, liberation of hexokinase 2, opening of mitochondrial permeability transition pore, upregulation of PINK1-PARKIN signaling, and eventual mitophagy-mediated cell death.

    “In vitro mechanism studies showed that I/R triggered a DRP1-dependent mitochondrial fragmentation, which subsequently led to oligomerization of voltage-dependent anion channel 1, liberation of hexokinase 2, opening of mitochondrial permeability transition pore, upregulation of PINK1–PARKIN signaling, and eventual mitophagy-mediated cell death [134].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Zhou, 2017, Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis, J. Pineal. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MOTS-c is a bioactive mitochondrial-derived peptide shown to activate the AMPK pathway and modulate metabolic homeostasis.

    “The mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) is a bioactive mitochondrial-derived peptide shown to activate the AMPK pathway and modulate metabolic homeostasis [193].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [193] Lee, 2015, The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nitrite activated protein kinase A, which in turn suppressed DRP1-dependent mitochondrial fission, augmented ΔΨm, and promoted superoxide production.

    “Further mechanism studies showed that nitrite activated protein kinase A, which in turn suppressed DRP1-dependent mitochondrial fission, augmented ΔΨm, and promoted superoxide production [135].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Mo, 2014, Nitrite activates protein kinase A in normoxia to mediate mitochondrial fusion and tolerance to ischaemia/reperfusion, Cardiovasc. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Melatonin promoted cell survival via AMPKα activation, accompanied by phosphor-DRP1-S616 reduction and phosphor-DRP1-S637 elevation, which normalized mitochondrial fission.

    “Melatonin promoted cell survival via AMPKα activation, accompanied by phosphor-DRP1-S616 reduction and phosphor-DRP1-S637 elevation, which normalized mitochondrial fission [134].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Zhou, 2017, Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis, J. Pineal. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Melatonin significantly decreased myocardial infarction, improved cardiac function, normalized blood flow, and lowered microcirculation perfusion impairment.

    “Melatonin significantly decreased myocadiac infarction, improved cardiac function, normalized blood flow, and lowered microcirculation perfusion impairment [134].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Zhou, 2017, Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis, J. Pineal. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of melatonin restored the endothelial barrier, promoted eNOS expression, decreased inflammatory cell infiltration, and lowered endothelial damage in cardiac microcirculation endothelial cells.

    “Histological analysis revealed that administration of melatonin restored the endothelial barrier, promoted eNOS expression, decreased inflammatory cell infiltration, and lowered endothelial damage in cardiac microcirculation endothelial cells [134].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Zhou, 2017, Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis, J. Pineal. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Phosphorylated AMPK increased and the expression of endothelin B and angiotensin II receptor type 1 receptors decreased after MOTS-c treatment.

    “In parallel, phosphorylated AMPK increased and the expression of endothelin B (ETB) and angiotensin II receptor type 1 (AT1) receptors decreased after MOTS-c treatment [136].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [136] Wei, 2020, Mitochondrial-derived peptide MOTS-c attenuates vascular calcification and secondary myocardial remodeling via adenosine monophosphate-activated protein kinase signaling pathway, Cardiorenal. Med. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    TSPO regulates neointimal formation after vascular injury via stimulating VSMC proliferation and migration, which is likely dependent on AMPK suppression.

    “These results indicate that TSPO regulates neointimal formation after vascular injury via stimulating VSMC proliferation and migration, which is likely dependent on AMPK suppression [137].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [137] Wu, 2020, TSPO ligands prevent the proliferation of vascular smooth muscle cells and attenuate neointima formation through AMPK activation, Acta Pharmacol. Sin. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neointimal hyperplasia narrows the luminal diameter, leading to decreased blood flow and recurrence of anginal symptoms.

    “Neointimal hyperplasia narrows the luminal diameter, leading to decreased blood flow and recurrence of anginal symptoms [196].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [196] Schwartz, 1997, Perspectives series: Cell adhesion in vascular biology. Smooth muscle migration in atherosclerosis and restenosis, J. Clin. Investig. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Prevention of mitochondrial fission restored the interaction between voltage-dependent anion channel 1 and hexokinase 2, stopped mitochondrial permeability transition pore opening, and PINK1-PARKIN activation, ultimately blunting cell death.

    “The prevention of mitochondrial fission further restored the interaction between voltage-dependent anion channel 1 and hexokinase 2, stopped mitochondrial permeability transition pore opening, and PINK1–PARKIN activation, ultimately blunting cell death [134].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Zhou, 2017, Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis, J. Pineal. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of AMPK activity is pro-hypertrophic because lines of molecular signaling pathways that control cell growth are attenuated by AMPK activation.

    “The loss of AMPK activity is believed to be pro-hypertrophic because lines of molecular signaling pathways that control cell growth are attenuated by AMPK activation [197,198,199].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [197] Chan, 2008, Resveratrol inhibits cardiac hypertrophy via AMP-activated protein kinase and Akt, J. Biol. Chem. source

      Not checked in the free run.

    • cites [198] Chan, 2004, Activation of AMP-activated protein kinase inhibits protein synthesis associated with hypertrophy in the cardiac myocyte, J. Biol. Chem. source

      Not checked in the free run.

    • cites [199] Browne, 2004, Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2 kinase and to its phosphorylation at a novel site, serine 398, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ROS scavenging blocks AMPK activation and blunts nitrite-induced cardioprotection after H/R.

    “Moreover, ROS scavenging blocks AMPK activation and blunts nitrite-induced cardioprotection after H/R [135].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Mo, 2014, Nitrite activates protein kinase A in normoxia to mediate mitochondrial fusion and tolerance to ischaemia/reperfusion, Cardiovasc. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DRP1-S616 phosphorylation was decreased, while DRP1-S637 phosphorylation was increased, ultimately leading to mitochondrial fission.

    “In the meantime, DRP1-S616 phosphorylation was decreased, while DRP1-S637 phosphorylation was increased, ultimately leading to mitochondrial fission [229].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [229] Zhou, 2018, Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission, Redox Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some pharmacological AMPK activators, such as MK-8722, cause cardiac hypertrophy, which is considered the main side effect of pharmacological pan-AMPK activation.

    “However, some pharmacological AMPK activators, such as MK-8722 [203], cause cardiac hypertrophy, which is considered the main side effect of pharmacological pan-AMPK activation [17].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [203] Feng, 2018, Discovery of MK-8722: A systemic, direct pan-activator of amp-activated protein kinase, ACS Med. Chem. Lett. source

      Not checked in the free run.

    • cites [17] Myers, 2017, Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In failing heart samples from patients or TAC mice, the isoform of AMPKα shifted from α2 to α1, which is associated with reduced mitophagy and dysfunctional mitochondria.

    “In failing heart samples from patients or TAC mice, the isoform of AMPKα shifted from α2 to α1, which is associated with reduced mitophagy and dysfunctional mitochondria [117].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Wang, 2018, AMPKalpha2 protects against the development of heart failure by enhancing mitophagy via pink1 phosphorylation, Circ. Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clusterin inhibits mitochondrial fragmentation while activating AMPK.

    “Clusterin, which exerts beneficial effects in ECs under diabetic conditions (both type 1 and type 2), inhibits mitochondrial fragmentation while activating AMPK [228].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [228] Ren, 2019, Clusterin ameliorates endothelial dysfunction in diabetes by suppressing mitochondrial fragmentation, Free Radic. Biol. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SIRT5 ablation attenuated cardiac hypertrophy and cardiac dysfunction in the TAC model, which is accompanied by the reduction of ATP, increase of AMP-to-ATP ratio, and enhancement of AMPK activity.

    “Consistently, SIRT5 ablation attenuated cardiac hypertrophy and cardiac dysfunction in the TAC model, which is accompanied by the reduction of ATP, increase of AMP-to-ATP ratio, and enhancement of AMPK activity [138].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] Zhang, M., Wu, J., Sun, R., Tao, X., Wang, X., Kang, Q., Wang, H., Zhang, L., Liu, P., and Zhang, J. (2019). SIRT5 deficiency suppresses mitochondrial ATP production and promotes AMPK activation in response to energy stress. PLoS ONE, 14. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endothelial dysfunction is attributed to many causes, including oxidative stress, chronic inflammation, and endothelium activation, in diabetes, which exhibits excessive free fatty acid, insulin resistance, and/or hyperglycemia.

    “Endothelial dysfunction is attributed to many causes, including oxidative stress, chronic inflammation, and endothelium activation, in diabetes, which exhibits excessive free fatty acid (FFA), insulin resistance, and/or hyperglycemia [216,217].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [216] Zhang, 2012, The link between metabolic abnormalities and endothelial dysfunction in type 2 diabetes: An update, Basic Res. Cardiol. source

      Not checked in the free run.

    • cites [217] Kim, 2006, Reciprocal relationships between insulin resistance and endothelial dysfunction: Molecular and pathophysiological mechanisms, Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SIRT5 deficiency attenuated ATP production from mitochondrial ETC, increased the AMP-to-ATP ratio, and in turn activated AMPK in both cultured cells and hearts under the conditions of energy stress.

    “SIRT5 deficiency attenuated ATP production from mitochondrial ETC, increased the AMP-to-ATP ratio, and in turn activated AMPK in both cultured cells and hearts under the conditions of energy stress [138].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] Zhang, M., Wu, J., Sun, R., Tao, X., Wang, X., Kang, Q., Wang, H., Zhang, L., Liu, P., and Zhang, J. (2019). SIRT5 deficiency suppresses mitochondrial ATP production and promotes AMPK activation in response to energy stress. PLoS ONE, 14. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both the conditions of hyperlipidemia and hyperglycemia impair mitochondrial dynamics by shifting the balance to excessive mitochondrial fission, leading to mitochondrial ROS over production and ETC impairment.

    “Both the conditions of hyperlipidemia and hyperglycemia impair mitochondrial dynamics by shifting the balance to excessive mitochondrial fission, leading to mitochondrial ROS over production and ETC impairment [221,222,223].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [221] LaRocca, 2014, Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice, J. Physiol. source

      Not checked in the free run.

    • cites [222] Huang, 2018, The uremic toxin hippurate promotes endothelial dysfunction via the activation of Drp1-mediated mitochondrial fission, Redox Biol. source

      Not checked in the free run.

    • cites [223] Yu, 2006, Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    SIRT5 controls cellular energy metabolism by AMPK activation upon energy stress, which further confirms the cardioprotective role of AMPK in left ventricular hypertrophy under the stress of pressure overload.

    “Thus, this study unveils a crucial role of SIRT5 in controlling cellular energy metabolism by AMPK activation upon energy stress, which further confirms the cardioprotective role of AMPK in left ventricular hypertrophy under the stress of pressure overload [138].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] Zhang, M., Wu, J., Sun, R., Tao, X., Wang, X., Kang, Q., Wang, H., Zhang, L., Liu, P., and Zhang, J. (2019). SIRT5 deficiency suppresses mitochondrial ATP production and promotes AMPK activation in response to energy stress. PLoS ONE, 14. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    MAMs play a vital role in lipid transport, Ca2+ signaling, cell survival, and energy metabolism, and have been implicated in diseases including Alzheimer's disease, cancer, lysosomal storage disease, diabetes mellitus, obesity, and metabolic disorders.

    “MAMs play a vital role in lipid transport, Ca2+ signaling, cell survival, and energy metabolism [234], and have been implicated in diseases including Alzheimer’s disease [235], cancer [236], lysosomal storage disease [237], diabetes mellitus [238,239], obesity, and metabolic disorders [240].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [234] Rowland, 2012, Endoplasmic reticulum-mitochondria contacts: Function of the junction, Nat. Rev. Mol. Cell Biol. source

      Not checked in the free run.

    • cites [235] Suski, 2017, Localization and processing of the amyloid-beta protein precursor in mitochondria-associated membranes, J. Alzheimers Dis.

      Not checked in the free run.

    • cites [236] Ando, 2018, Remodeling of Ca(2+) signaling in cancer: Regulation of inositol 1,4,5-trisphosphate receptors through oncogenes and tumor suppressors, Adv. Biol. Regul. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High glucose-driven inactivation of AMPK increased FUNDC1, resulting in aberrant MAM formation, mitochondrial Ca2+ increase, mitochondrial dysfunction, and cardiac dysfunction.

    “High glucose-driven inactivation of AMPK increased FUNDC1, resulting in aberrant MAM formation, mitochondrial Ca2+ increase, mitochondrial dysfunction, and cardiac dysfunction [139].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [139] Wu, 2019, Hyperglycemia-Driven Inhibition of AMP-activated protein kinase alpha2 induces diabetic cardiomyopathy by promoting mitochondria-associated endoplasmic reticulum membranes in vivo, Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upregulation of XO was accompanied by excessive ROS production, resulting in the Ser616 phosphorylation as well as the mitochondrial migration of DRP1.

    “Upregulation of XO was accompanied by excessive ROS production, resulting in the Ser616 phosphorylation as well as the mitochondrial migration of DRP1 [140].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] Cui, 2018, Melatonin alleviates inflammation-induced apoptosis in human umbilical vein endothelial cells via suppression of Ca(2+)-XO-ROS-Drp1-mitochondrial fission axis by activation of AMPK/SERCA2a pathway, Cell Stress Chaperones source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vildagliptin improved mitochondrial dysfunction in diabetic endothelial cells, possibly by blunting DRP1-dependent mitochondrial fission by inducing AMPK activation.

    “Vildagliptin improved mitochondrial dysfunction in diabetic ECs, possibly by blunting DRP1-dependent mitochondrial fission by inducing AMPK activation [230].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [230] Liu, 2019, Vildagliptin improves high glucose-induced endothelial mitochondrial dysfunction via inhibiting mitochondrial fission, J. Cell. Mol. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under diabetic conditions, endothelial cells often have reduced eNOS activity and diminished NO production.

    “Thus, under diabetic conditions, ECs often have reduced eNOS activity and diminished NO production [259].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [259] Dresner, 1999, Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity, J. Clin. Investig. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Melatonin activated AMPK, which was associated with the upregulation of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a.

    “Importantly, melatonin activated AMPK, which was associated with the upregulation of sarcoplasmic/endoplasmic reticulum calcium ATPase 2a [140].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] Cui, 2018, Melatonin alleviates inflammation-induced apoptosis in human umbilical vein endothelial cells via suppression of Ca(2+)-XO-ROS-Drp1-mitochondrial fission axis by activation of AMPK/SERCA2a pathway, Cell Stress Chaperones source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Obesity-related type 2 diabetes patients often have elevated plasma FFAs, because of either increased amounts of FFAs released from large amounts of adipose tissue or impaired FFA clearance.

    “Obesity-related type 2 diabetes patients often have elevated plasma FFAs, because of either increased amounts of FFAs released from large amounts of adipose tissue or impaired FFA clearance [258].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [258] Boden, 2003, Effects of free fatty acids (FFA) on glucose metabolism: Significance for insulin resistance and type 2 diabetes, Exp. Clin. Endocrinol. Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Melatonin-activated AMPK-sarcoplasmic/endoplasmic reticulum calcium ATPase 2a axis prevented calcium overload, XO-dependent ROS overproduction, DRP1-mediated mitochondrial fission, and apoptosis in lipopolysaccharide-treated cells.

    “Further, melatonin-activated AMPK-sarcoplasmic/endoplasmic reticulum calcium ATPase 2a axis prevented calcium overload, XO-dependent ROS overproduction, DRP1-mediated mitochondrial fission, and apoptosis in lipopolysaccharide-treated cells [140].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] Cui, 2018, Melatonin alleviates inflammation-induced apoptosis in human umbilical vein endothelial cells via suppression of Ca(2+)-XO-ROS-Drp1-mitochondrial fission axis by activation of AMPK/SERCA2a pathway, Cell Stress Chaperones source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lipopolysaccharide triggered cytosolic calcium overload, and in turn upregulated XO, whose activity is calcium-dependent.

    “Lipopolysaccharide triggered cytosolic calcium overload, and in turn upregulated XO, whose activity is calcium-dependent [140].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [140] Cui, 2018, Melatonin alleviates inflammation-induced apoptosis in human umbilical vein endothelial cells via suppression of Ca(2+)-XO-ROS-Drp1-mitochondrial fission axis by activation of AMPK/SERCA2a pathway, Cell Stress Chaperones source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FUNDC1 is essential for maintaining the MAM structure and ensuring appropriate Ca2+ transfer from the sarcoplasmic reticulum to mitochondria in healthy hearts.

    “Study showed that mitochondrial outer membrane protein FUN14 domain containing 1 (FUNDC1) is essential for maintaining the MAM structure and ensuring appropriate Ca2+ transfer from the sarcoplasmic reticulum (i.e., ER in myocytes) to mitochondria in healthy hearts [241].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [241] Wu, 2017, Binding of FUN14 domain containing 1 with inositol 1,4,5-trisphosphate receptor in mitochondria-associated endoplasmic reticulum membranes maintains mitochondrial dynamics and function in hearts in vivo, Circulation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Corosolic acid activated AMPK in a LKB1-dependent manner, and AMPK silencing abrogated its inhibitory effect on DRP1 activation and mitochondrial fission.

    “CRA activated AMPK in a LKB1-dependent manner, and AMPK silencing abrogated its inhibitory effect on DRP1 activation and mitochondrial fission [141].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [141] Li, 2016, Inhibition of mitochondrial fission and NOX2 expression prevent nlrp3 inflammasome activation in the endothelium: The role of corosolic acid action in the amelioration of endothelial dysfunction, Antioxid. Redox Signal. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DRP1 knockdown attenuated PA-induced NOX2 activation, and knockdown of DRP1 or NOX2 suppressed PA-induced NLRP3 inflammatory effect and strengthened the inhibitory effects of corosolic acid.

    “DRP1 knockdown attenuated PA-induced NOX2 activation, and knockdown of DRP1 or NOX2 suppressed PA-induced NACHT, LRR, and PYD domains-containing protein 3 inflammatory effect and, in the meantime, strengthened the inhibitory effects of CRA [141].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [141] Li, 2016, Inhibition of mitochondrial fission and NOX2 expression prevent nlrp3 inflammasome activation in the endothelium: The role of corosolic acid action in the amelioration of endothelial dysfunction, Antioxid. Redox Signal. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Obesity is closely associated with cardiac disorders, which is assumed to be a consequence of the adaption to an oversupply of high-fat substrates.

    “Obesity is closely associated with cardiac disorders, which is assumed to be a consequence of the adaption to an oversupply of high-fat substrates [262,263].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [262] Harmancey, 2008, Adaptation and maladaptation of the heart in obesity, Hypertension source

      Not checked in the free run.

    • cites [263] Louwe, 2012, Gender-dependent effects of high-fat lard diet on cardiac function in C57Bl/6J mice, Appl. Physiol. Nutr. Metab. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    AMPK activation plays protective roles across diverse cardiovascular diseases.

    “It is well-accepted that AMPK activation plays protective roles across diverse CVDs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Corosolic acid prevented mitochondrial fission by regulating DRP1 phosphorylation at Ser637 in an AMPK-dependent manner, contributing to the blockage of NOX2-related oxidative stress and suppressing NLRP3 inflammasome in the endothelium.

    “These data collectively demonstrated that CRA prevented mitochondrial fission by regulating DRP1 phosphorylation at Ser637 in an AMPK-dependent manner, contributing to the blockage of NOX2-related oxidative stress and suppressing NACHT, LRR, and PYD domains-containing protein 3 inflammasome in the endothelium [141].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [141] Li, 2016, Inhibition of mitochondrial fission and NOX2 expression prevent nlrp3 inflammasome activation in the endothelium: The role of corosolic acid action in the amelioration of endothelial dysfunction, Antioxid. Redox Signal. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    Structural and functional changes to mitochondria may be amplified under disease conditions.

    “Far beyond our current knowledge are the structural and functional changes to mitochondria that may be amplified under disease conditions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    AMPK has emerged as a guardian of mitochondria because almost all mitochondrial insults can activate AMPK.

    “AMPK has emerged as a guardian of mitochondria because almost all mitochondrial insults can activate AMPK.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    The interplay within the AMPK-mitochondrial axis during the initiation and progression of cardiovascular diseases is poorly investigated.

    “However, the interplay within the AMPK–mitochondrial axis during the initiation and progression of CVDs is poorly investigated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Pomegranate extract activated AMPK, which may be responsible for the intervention of mitochondrial loss through promoting mitochondrial biogenesis and the attenuation of oxidative stress by means of upregulating phase II enzymes in HFD hearts.

    “Concomitantly, pomegranate extract activated AMPK, which may be responsible for the intervention of mitochondrial loss through promoting mitochondrial biogenesis and the attenuation of oxidative stress by means of upregulating phase II enzymes in HFD hearts [142].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [142] Cao, 2015, Punicalagin, an active component in pomegranate, ameliorates cardiac mitochondrial impairment in obese rats via AMPK activation, Sci. Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A direct functional connection between AMPK signaling and β-adrenergic responsiveness exists in the heart, and AMPK might be a valuable target to recover the decreased β-adrenergic responsive in the heart of obesity.

    “A direct functional connection between AMPK signaling and β-adrenergic responsiveness exists in the heart, and AMPK might be a valuable target to recover the decreased β-adrenergic responsive in the heart of obesity [270].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [270] Bussey, 2018, Cardiac beta-adrenergic responsiveness of obese Zucker rats: The role of AMPK, Exp. Physiol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Limited evidence has focused on mitochondrial dynamics, mitochondrial biogenesis, and mitophagy, the three common functions of mitochondria that have been studied by cell biologists.

    “Limited evidence has focused on mitochondrial dynamics, mitochondrial biogenesis, and mitophagy, the three common functions of mitochondria that have been studied by cell biologists.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Punicalagin protects against HFD-induced cardiac disorders by activating AMPK pathway and promoting mitochondrial biogenesis.

    “Punicalagin, the major active component in pomegranate extract, protects against HFD-induced cardiac disorders by activating AMPK pathway and promoting mitochondrial biogenesis [142].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [142] Cao, 2015, Punicalagin, an active component in pomegranate, ameliorates cardiac mitochondrial impairment in obese rats via AMPK activation, Sci. Rep. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The loss of AMPK activity exacerbated cardiac hypertrophy and dysfunctional contractility of HFD-fed mice.

    “The loss of AMPK activity exacerbated cardiac hypertrophy and dysfunctional contractility of HFD-fed mice [268].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [268] Turdi, 2011, Deficiency in AMP-activated protein kinase exaggerates high fat diet-induced cardiac hypertrophy and contractile dysfunction, J. Mol. Cell. Cardiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    C1q/tumor necrosis factor-related protein 9 exhibited anti-myocardial lipotoxicity effects and attenuated cardiac hypertrophy, likely via activation of the LKB1-AMPK signaling.

    “C1q/tumor necrosis factor-related protein 9 exhibited anti-myocardial lipotoxicity effects and attenuated cardiac hypertrophy, likely via activation of the LKB1–AMPK signaling [269].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [269] Zuo, 2020, CTRP9 knockout exaggerates lipotoxicity in cardiac myocytes and high-fat diet-induced cardiac hypertrophy through inhibiting the LKB1/AMPK pathway, J. Cell. Mol. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased body weight switches the substrate of the heart from fatty acid to sugar, resulting in fat accumulation around the heart and eventually inducing cardiac impairment and increasing the risk of MI.

    “Increased body weight switches the substrate of the heart from fatty acid to sugar, resulting in fat accumulation around the heart and eventually inducing cardiac impairment and increasing the risk of MI [264,265].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [264] Schram, 2008, Implications of myocardial matrix remodeling by adipokines in obesity-related heart failure, Trends Cardiovasc. Med. source

      Not checked in the free run.

    • cites [265] Look, 2009, Adipocyte fatty acid-binding protein suppresses cardiomyocyte contraction: A new link between obesity and heart disease, Circ. Res. source

      Not checked in the free run.

86 of 86

  • The paper relies on this without support.

    Mitochondria are the primary source of ATP production in the cell.

    “Mitochondria are considered the primary source of ATP production in the cell.”

  • The paper relies on this without support.

    Mitochondrial dysfunction occurs in the development of many cardiovascular diseases owing to production of ROS beyond control.

    “Mitochondrial dysfunction occurs in the development of many CVDs such as atherosclerosis, ischemia-reperfusion (I/R) injury, hypertension, diabetes, cardiac hypertrophy, and heart failure (HF), owing to the production of ROS beyond control.”

  • The paper relies on this without support.

    AMPK is widely expressed in the cardiovascular system.

    “AMPK is widely expressed in the cardiovascular system.”

  • The paper relies on this without support.

    The α1 isoform predominates in VSMCs, ECs, adipocytes, and monocytes/macrophages, whereas cardiomyocytes express much higher amounts of the α2 isoform.

    “The α1 isoform predominates in VSMCs, ECs, adipocytes, and monocytes/macrophages, whereas cardiomyocytes express much higher amounts of the α2 isoform.”

  • The paper relies on this without support.

    Aberrant AMPK signaling is involved in the pathogenesis of various cardiovascular diseases, including hypertension, atherosclerosis, and stroke.

    “Moreover, aberrant AMPK signaling is involved in the pathogenesis of various CVDs, including hypertension, atherosclerosis, and stroke.”

  • The paper relies on this without support.

    Oxidative stress caused by risk factors represents a major contributor to endothelial dysfunction as a common predisposing condition to atherosclerosis.

    “Oxidative stress caused by risk factors represents a major contributor to endothelial dysfunction as a common predisposing condition to atherosclerosis.”

  • The paper relies on this without support.

    UCP2 appears to have a main function of controlling ROS generation in diabetes, obesity, and atherosclerosis.

    “It appears that UCP2 has a main function of controlling ROS generation in diabetes, obesity, and atherosclerosis, although it was originally considered as a modulator of nonshivering thermogenesis.”

  • The paper relies on this without support.

    Rapid Ca2+ influx into mitochondrial matrix occurs through the mitochondrial Ca2+ uniporter, a specific channel located at the inner mitochondrial membrane.

    “It is well established that rapid Ca2+ influx into mitochondrial matrix occurs through the mitochondrial Ca2+ uniporter (MCU), a specific channel located at the inner mitochondrial membrane.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • AMPK activators such as metformin and berberine improve mitochondrial efficiency and energy substrate utilization, which can reduce fatigue and increase endurance capacity.

    “For example, AMPK activators such as metformin and berberine improve mitochondrial efficiency and energy substrate utilization, which can reduce fatigue and increase endurance capacity”

    From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [106]

    Section 3.1 identifies metformin and berberine as agents that induce AMPK activation, and section 4.1 describes AMPK’s role in mitochondrial biogenesis. The paper does not establish that these two drugs improve mitochondrial efficiency or energy-substrate utilization, or that they reduce fatigue or increase endurance capacity. Pages are not specified in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Metformin and berberine activate AMPK, promoting fatty acid oxidation, mitochondrial biogenesis, and improved insulin sensitivity.

    “For example, metformin and berberine activate AMPK, promoting fatty acid oxidation, mitochondrial biogenesis, and improved insulin sensitivity”

    From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [106]

    Section 3.2 reports that both drugs activate AMPK and that berberine improves insulin sensitivity in type 2 diabetes models. Section 2.2 links metformin-induced AMPK activation to mitochondrial biogenesis, and section 4.1 describes AMPK as a promoter of mitochondrial biogenesis generally. Our copy does not establish that both drugs promote fatty acid oxidation or that berberine promotes mitochondrial biogenesis through AMPK. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Empagliflozin is said both to inhibit and to cause mitochondrial fission

    Minor

    The passage attributes empagliflozin's protective effect to inhibition of mitochondrial fission, but then says its associated phosphorylation changes ultimately lead to mitochondrial fission.

  • Melatonin is said both to prevent and to induce endothelial apoptosis

    Minor

    The paragraph first says melatonin protects endothelial cells against inflammation-mediated apoptosis, but its concluding sentence says melatonin induces that apoptosis.

  • MFF phosphorylation site differs between adjacent statements

    Minor

    One statement identifies Ser155 and Ser173 as the two MFF sites phosphorylated by AMPK; the next identifies Ser155 and Ser172. The second site is inconsistent.

3 of 3

Cites

5 retracted

Flagged first, then by citations

3 of the 278 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Wu, S., & Zou, M.-H.
Affiliations
Georgia State University (US)
Corresponding author
Wu, Shengnan
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2020-07-15
Volume
21
Issue
14
Pages
4987
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms21144987
PMC
PMC7404275
OpenAlex
W3043111807
Cited by
286
References
278
Citations by year
2026: 48 · 2025: 71 · 2024: 50 · 2023: 45 · 2022: 43 · 2021: 27 · 2020: 2
FWCI
2.80
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • American Heart Association (16POST29960011, 19CDA34760110)
  • Georgia Research Alliance
  • National Institutes of Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Keywords
AMPK, mitochondrial dysfunction, mitochondrial homeostasis, cardiovascular disease, redox sensing, energy homeostasis, statins, metformin, berberine, polyphenols, resveratrol
MeSH terms
Adenosine Triphosphate, Animals, Cardiovascular Diseases, Energy Metabolism, Humans, Mitochondria, Reactive Oxygen Species, AMP-Activated Protein Kinases, Mitochondrial Turnover

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review