Mitochondrial dysfunction in insulin resistance: differential contributions of chronic insulin and saturated fatty acid exposure in muscle cells

Mitochondrial dysfunction has been associated with insulin resistance, obesity and diabetes. Hyperinsulinaemia and hyperlipidaemia are hallmarks of the insulin-resistant state. We sought to determine the contributions of high insulin and saturated fatty acid exposure to mitochondrial function and biogenesis in cultured myocytes. Differentiated C2C12 myotubes were left untreated or exposed to chronic high insulin or high palmitate. Mitochondrial function was determined assessing: oxygen consumption, mitochondrial membrane potential, ATP content and ROS (reactive oxygen species) production. We also determined the expression of several mitochondrial genes. Chronic insulin treatment of myotubes caused insulin resistance with reduced PI3K (phosphoinositide 3-kinase) and ERK (extracellular-signal-regulated kinase) signalling. Insulin treatment increased oxygen consumption but reduced mitochondrial membrane potential and ROS production. ATP cellular levels were maintained through an increased glycolytic rate. The expression of mitochondrial OXPHOS (oxidative phosphorylation) subunits or Mfn-2 (mitofusin 2) were not significantly altered in comparison with untreated cells, whereas expression of PGC-1α (peroxisome-proliferator-activated receptor γ co-activator-1α) and UCPs (uncoupling proteins) were reduced. In contrast, saturated fatty acid exposure caused insulin resistance, reducing PI3K (phosphoinositide 3-kinase) and ERK (extracellular-signal-regulated kinase) activation while increasing activation of stress kinases JNK (c-Jun N-terminal kinase) and p38. Fatty acids reduced oxygen consumption and mitochondrial membrane potential while up-regulating the expression of mitochondrial ETC (electron chain complex) protein subunits and UCP proteins. Mfn-2 expression was not modified by palmitate. Palmitate-treated cells also showed a reduced glycolytic rate. Taken together, our findings indicate that chronic insulin and fatty acid-induced insulin resistance differentially affect mitochondrial function. In both conditions, cells were able to maintain ATP levels despite the loss of membrane potential; however, different protein expression suggests different adaptation mechanisms.

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Two Subpopulations of Human Monocytes That Differ by Mitochondrial Membrane Potential

Biomedicines ◽

10.3390/biomedicines9020153 ◽

2021 ◽

Vol 9 (2) ◽

pp. 153

Author(s):

Nikita G. Nikiforov ◽

Anastasia Ryabova ◽

Marina V. Kubekina ◽

Igor D. Romanishkin ◽

Kirill A. Trofimov ◽

...

Keyword(s):

Membrane Potential ◽

Primary Culture ◽

Mitochondrial Membrane Potential ◽

Mitochondrial Function ◽

Mitochondrial Membrane ◽

Aminolevulinic Acid ◽

Protoporphyrin Ix ◽

Intima Media Thickness ◽

Mtdna Mutations ◽

Proinflammatory Activity

Atherosclerosis is associated with a chronic local inflammatory process in the arterial wall. Our previous studies have demonstrated the altered proinflammatory activity of circulating monocytes in patients with atherosclerosis. Moreover, atherosclerosis progression and monocyte proinflammatory activity were associated with mitochondrial DNA (mtDNA) mutations in circulating monocytes. The role of mitochondria in the immune system cells is currently well recognized. They can act as immunomodulators by releasing molecules associated with bacterial infection. We hypothesized that atherosclerosis can be associated with changes in the mitochondrial function of circulating monocytes. To test this hypothesis, we performed live staining of the mitochondria of CD14+ monocytes from healthy donors and atherosclerosis patients with MitoTracker Orange CMTMRos dye, which is sensitive to mitochondrial membrane potential. The intensity of such staining reflects mitochondrial functional activity. We found that parts of monocytes in the primary culture were characterized by low MitoTracker staining (MitoTracker-low monocytes). Such cells were morphologically similar to cells with normal staining and able to metabolize 5-aminolevulinic acid and accumulate the heme precursor protoporphyrin IX (PplX), indicative of partially preserved mitochondrial function. We assessed the proportion of MitoTracker-low monocytes in the primary culture for each study subject and compared the results with other parameters, such as monocyte ability to lipopolysaccharide (LPS)-induced proinflammatory activation and the intima-media thickness of carotid arteries. We found that the proportion of MitoTracker-low monocytes was associated with the presence of atherosclerotic plaques. An increased number of such monocytes in the primary culture was associated with a reduced proinflammatory activation ability of cells. The obtained results indicate the presence of circulating monocytes with mitochondrial dysfunction and the association of such cells with chronic inflammation and atherosclerosis development.

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Genomic instability induced by radiation-mimicking chemicals is not associated with persistent mitochondrial degeneration

Radiation and Environmental Biophysics ◽

10.1007/s00411-021-00927-5 ◽

2021 ◽

Author(s):

Luukkonen Jukka ◽

Höytö Anne ◽

Sokka Miiko ◽

Syväoja Juhani ◽

Juutilainen Jukka ◽

...

Keyword(s):

Membrane Potential ◽

Ionizing Radiation ◽

Genomic Instability ◽

Mitochondrial Membrane Potential ◽

Mitochondrial Function ◽

Mitochondrial Membrane ◽

Neuroblastoma Cells ◽

Superoxide Production ◽

Mitochondrial Activity ◽

Mitochondrial Superoxide

AbstractIonizing radiation has been shown to cause induced genomic instability (IGI), which is defined as a persistently increased rate of genomic damage in the progeny of the exposed cells. In this study, IGI was investigated by exposing human SH-SY5Y neuroblastoma cells to hydroxyurea and zeocin, two chemicals mimicking different DNA-damaging effects of ionizing radiation. The aim was to explore whether IGI was associated with persistent mitochondrial dysfunction. Changes to mitochondrial function were assessed by analyzing mitochondrial superoxide production, mitochondrial membrane potential, and mitochondrial activity. The formation of micronuclei was used to determine immediate genetic damage and IGI. Measurements were performed either immediately, 8 days, or 15 days following exposure. Both hydroxyurea and zeocin increased mitochondrial superoxide production and affected mitochondrial activity immediately after exposure, and mitochondrial membrane potential was affected by zeocin, but no persistent changes in mitochondrial function were observed. IGI became manifested 15 days after exposure in hydroxyurea-exposed cells. In conclusion, immediate responses in mitochondrial function did not cause persistent dysfunction of mitochondria, and this dysfunction was not required for IGI in human neuroblastoma cells.

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Palmitic Acid, but Not Lauric Acid, Induces Metabolic Inflammation, Mitochondrial Fragmentation, and a Drop in Mitochondrial Membrane Potential in Human Primary Myotubes

Frontiers in Nutrition ◽

10.3389/fnut.2021.663838 ◽

2021 ◽

Vol 8 ◽

Author(s):

Domenico Sergi ◽

Natalie Luscombe-Marsh ◽

Nenad Naumovski ◽

Mahinda Abeywardena ◽

Nathan O'Callaghan

Keyword(s):

Insulin Resistance ◽

Membrane Potential ◽

Electron Transport ◽

Mitochondrial Membrane Potential ◽

Electron Transport Chain ◽

Mitochondrial Membrane ◽

Chain Complex ◽

Mitochondrial Fragmentation ◽

Metabolic Inflammation ◽

Transport Chain

The chain length of saturated fatty acids may dictate their impact on inflammation and mitochondrial dysfunction, two pivotal players in the pathogenesis of insulin resistance. However, these paradigms have only been investigated in animal models and cell lines so far. Thus, the aim of this study was to compare the effect of palmitic (PA) (16:0) and lauric (LA) (12:0) acid on human primary myotubes mitochondrial health and metabolic inflammation. Human primary myotubes were challenged with either PA or LA (500 μM). After 24 h, the expression of interleukin 6 (IL-6) was assessed by quantitative polymerase chain reaction (PCR), whereas Western blot was used to quantify the abundance of the inhibitor of nuclear factor κB (IκBα), electron transport chain complex proteins and mitofusin-2 (MFN-2). Mitochondrial membrane potential and dynamics were evaluated using tetraethylbenzimidazolylcarbocyanine iodide (JC-1) and immunocytochemistry, respectively. PA, contrarily to LA, triggered an inflammatory response marked by the upregulation of IL-6 mRNA (11-fold; P < 0.01) and a decrease in IκBα (32%; P < 0.05). Furthermore, whereas PA and LA did not differently modulate the levels of mitochondrial electron transport chain complex proteins, PA induced mitochondrial fragmentation (37%; P < 0.001), decreased MFN-2 (38%; P < 0.05), and caused a drop in mitochondrial membrane potential (11%; P < 0.01) compared to control, with this effect being absent in LA-treated cells. Thus, LA, as opposed to PA, did not trigger pathogenetic mechanisms proposed to be linked with insulin resistance and therefore represents a healthier saturated fatty acid choice to potentially preserve skeletal muscle metabolic health.

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Cultured hypothalamic neurons are resistant to inflammation and insulin resistance induced by saturated fatty acids

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00006.2010 ◽

2010 ◽

Vol 298 (6) ◽

pp. E1122-E1130 ◽

Cited By ~ 51

Author(s):

Sun Ju Choi ◽

Francis Kim ◽

Michael W. Schwartz ◽

Brent E. Wisse

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Fatty Acid ◽

Saturated Fatty Acid ◽

Cell Lines ◽

Saturated Fatty Acids ◽

Neuronal Cell ◽

Acid Exposure ◽

Inflammatory Signaling ◽

Hypothalamic Neurons

Hypothalamic inflammation induced by high-fat feeding causes insulin and leptin resistance and contributes to the pathogenesis of obesity. Since in vitro exposure to saturated fatty acids causes inflammation and insulin resistance in many cultured cell types, we determined how cultured hypothalamic neurons respond to this stimulus. Two murine hypothalamic neuronal cell cultures, N43/5 and GT1–7, were exposed to escalating concentrations of saturated fatty acids for up to 24 h. Harvested cells were evaluated for activation of inflammation by gene expression and protein content. Insulin-treated cells were evaluated for induction of markers of insulin receptor signaling (p-IRS, p-Akt). In both hypothalamic cell lines, inflammation was induced by prototypical inflammatory mediators LPS and TNFα, as judged by induction of IκBα (3- to 5-fold) and IL-6 (3- to 7-fold) mRNA and p-IκBα protein, and TNFα pretreatment reduced insulin-mediated p-Akt activation by 30% ( P < 0.05). By comparison, neither mixed saturated fatty acid (100, 250, or 500 μM for ≤6 h) nor palmitate exposure alone (200 μM for ≤24 h) caused inflammatory activation or insulin resistance in cultured hypothalamic neurons, whereas they did in control muscle and endothelial cell lines. Despite the lack of evidence of inflammatory signaling, saturated fatty acid exposure in cultured hypothalamic neurons causes endoplasmic reticulum stress, induces mitogen-activated protein kinase, and causes apoptotic cell death with prolonged exposure. We conclude that saturated fatty acid exposure does not induce inflammatory signaling or insulin resistance in cultured hypothalamic neurons. Therefore, hypothalamic neuronal inflammation in the setting of DIO may involve an indirect mechanism mediated by saturated fatty acids on nonneuronal cells.

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Abstract P352: Prostaglandin E2 Reduces Mitochondrial Function in Adult Mouse Cardiomyocytes

Hypertension ◽

10.1161/hyp.70.suppl_1.p352 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Pamela Harding ◽

Timothy D Bryson ◽

Indrani Datta ◽

Yun Wang ◽

Albert Levin

Keyword(s):

Membrane Potential ◽

Ejection Fraction ◽

Prostaglandin E2 ◽

Mitochondrial Membrane Potential ◽

Mitochondrial Function ◽

Complex I ◽

Mitochondrial Membrane ◽

Receptor Subtypes ◽

Atp Levels ◽

Complex I Activity

Hypertension is a leading cause of heart failure and both conditions are characterized by increased prostaglandin E2 (PGE2) which signals through 4 receptor subtypes (EP1-EP4) to elicit diverse physiologic effects. We previously reported that cardiomyocyte-specific deletion of the EP4 receptor results in a phenotype of dilated cardiomyopathy in male mice that is characterized by reduced ejection fraction. Subsequent gene array on left ventricles from these mice, coupled with Ingenuity Pathway Analysis (IPA) demonstrated that genes differentiating WT mice and EP4 KO mice with low ejection fraction were significantly overrepresented in mitochondrial (p=2.51x10 -28 ) and oxidative phosphorylation (p=3.16 x10 -30 ) pathways. We therefore hypothesized that PGE2 could reduce mitochondrial function. To test this hypothesis, we used isolated mouse cardiomyocytes (AVM) from 16-18 week old male C57Bl/6 mice and treated them with 1 μM PGE2 for various times. Mitochondrial gene expression was examined using a RT-profiler kit for mitochondrial energy metabolism, complex I activity with a spectrophotometric assay, ATP levels with a bioluminescence assay and mitochondrial membrane potential using JC-1 staining. Treatment of AVM with PGE2 for 4 hrs reduced expression of multiple genes from mitochondrial pathways including sub units of mitochondrial NADH dehydrogenase ubiquinone flavoprotein (Nduf), a component of complex I. In accord with the mRNA data, Complex I activity was reduced by 50% (p < 0.05) by 4 hr treatment with PGE2, from 1.32 ± 0.36 to 0.66 ± 0.08 mOD/min. Cytochrome c oxidase subunit 8 (Cox8c) mRNA was also reduced from a control value of 1.00 to -1.75 ± 0.20 (p < 0.005) after PGE2 treatment. Immuno-fluorescence showed that JC-1 aggregates were reduced after 1 or 3 hr treatment with either 1 μM PGE2 or the EP3 agonist, sulprostone, suggesting reduced mitochondrial membrane potential. Subsequent experiments also showed that ATP levels were reduced 16% from 11.18 ± 0.71 nmol to 9.39 ± 0.83 nmol after treatment with sulprostone for only 1 hr. Taken together, these results suggest that increased PGE2 in hypertension may contribute to impaired mitochondrial function and provide yet another link between inflammation and cardiac dysfunction.

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Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons

International Journal of Molecular Sciences ◽

10.3390/ijms21010220 ◽

2019 ◽

Vol 21 (1) ◽

pp. 220 ◽

Cited By ~ 4

Author(s):

Han-A Park ◽

Nelli Mnatsakanyan ◽

Katheryn Broman ◽

Abigail U. Davis ◽

Jordan May ◽

...

Keyword(s):

Membrane Potential ◽

Mitochondrial Dysfunction ◽

Mitochondrial Membrane Potential ◽

Mitochondrial Function ◽

Hippocampal Neurons ◽

Mitochondrial Membrane ◽

Antioxidant Properties ◽

B Cell Lymphoma ◽

Atp Depletion ◽

Primary Hippocampal Neurons

B-cell lymphoma-extra large (Bcl-xL) is an anti-apoptotic member of the Bcl2 family of proteins, which supports neurite outgrowth and neurotransmission by improving mitochondrial function. During excitotoxic stimulation, however, Bcl-xL undergoes post-translational cleavage to ∆N-Bcl-xL, and accumulation of ∆N-Bcl-xL causes mitochondrial dysfunction and neuronal death. In this study, we hypothesized that the generation of reactive oxygen species (ROS) during excitotoxicity leads to formation of ∆N-Bcl-xL. We further proposed that the application of an antioxidant with neuroprotective properties such as α-tocotrienol (TCT) will prevent ∆N-Bcl-xL-induced mitochondrial dysfunction via its antioxidant properties. Primary hippocampal neurons were treated with α-TCT, glutamate, or a combination of both. Glutamate challenge significantly increased cytosolic and mitochondrial ROS and ∆N-Bcl-xL levels. ∆N-Bcl-xL accumulation was accompanied by intracellular ATP depletion, loss of mitochondrial membrane potential, and cell death. α-TCT prevented loss of mitochondrial membrane potential in hippocampal neurons overexpressing ∆N-Bcl-xL, suggesting that ∆N-Bcl-xL caused the loss of mitochondrial function under excitotoxic conditions. Our data suggest that production of ROS is an important cause of ∆N-Bcl-xL formation and that preventing ROS production may be an effective strategy to prevent ∆N-Bcl-xL-mediated mitochondrial dysfunction and thus promote neuronal survival.

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Melatonin and Nicotinamide Mononucleotide Attenuate Myocardial Ischemia/Reperfusion Injury via Modulation of Mitochondrial Function and Hemodynamic Parameters in Aged Rats

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/1074248419882002 ◽

2019 ◽

Vol 25 (3) ◽

pp. 240-250 ◽

Cited By ~ 10

Author(s):

Leila Hosseini ◽

Manouchehr S. Vafaee ◽

Reza Badalzadeh

Keyword(s):

Oxidative Stress ◽

Membrane Potential ◽

Mitochondrial Membrane Potential ◽

Mitochondrial Function ◽

Mitochondrial Membrane ◽

Ischemia Reperfusion ◽

Combined Therapy ◽

Aged Rats ◽

Hemodynamic Parameters ◽

Nicotinamide Mononucleotide

Ischemic heart diseases are the major reasons for disability and mortality in elderly individuals. In this study, we tried to examine the combined effects of nicotinamide mononucleotide (NMN) preconditioning and melatonin postconditioning on cardioprotection and mitochondrial function in ischemia/reperfusion (I/R) injury of aged male rats. Sixty aged Wistar rats were randomly allocated to 5 groups, including sham, control, NMN-receiving, melatonin-receiving, and combined therapy (NMN+melatonin). Isolated hearts were mounted on Langendorff apparatus and then underwent 30-minue ligation of left anterior descending coronary artery to induce regional ischemic insult, followed by 60 minutes of reperfusion. Nicotinamide mononucleotide (100 mg/kg/d intraperitoneally) was administered for every other day for 28 days before I/R. Melatonin added to perfusion solution, 5 minutes prior to the reperfusion up to 15 minutes early reperfusion. Myocardial hemodynamic and infarct size (IS) were measured, and the left ventricles samples were obtained to evaluate cardiac mitochondrial function and oxidative stress markers. Melatonin postconditioning and NMN had significant cardioprotective effects in aged rats; they could improve hemodynamic parameters and reduce IS and lactate dehydrogenase release compared to those of control group. Moreover, pretreatment with NMN increased the cardioprotection by melatonin. All treatments reduced oxidative stress and mitochondrial reactive oxygen species (ROS) levels and improved mitochondrial membrane potential and restored NAD+/NADH ratio. The effects of combined therapy on reduction of mitochondrial ROS and oxidative status and improvement of mitochondrial membrane potential were greater than those of alone treatments. Combination of melatonin and NMN can be a promising strategy to attenuate myocardial I/R damages in aged hearts. Restoration of mitochondrial function may substantially contribute to this cardioprotection.

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The spatio-temporal dynamics of mitochondrial membrane potential during oocyte maturation

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaz055 ◽

2019 ◽

Vol 25 (11) ◽

pp. 695-705 ◽

Cited By ~ 5

Author(s):

Usama AL-Zubaidi ◽

Jun Liu ◽

Ozgur Cinar ◽

Rebecca L Robker ◽

Deepak Adhikari ◽

...

Keyword(s):

Membrane Potential ◽

Mitochondrial Membrane Potential ◽

Oocyte Maturation ◽

Mitochondrial Function ◽

Mitochondrial Membrane ◽

Local Level ◽

Meiotic Spindle ◽

Mitochondrial Activity ◽

Wide Range ◽

Spatio Temporal

Abstract Mitochondria are highly dynamic organelles and their distribution, structure and activity affect a wide range of cellular functions. Mitochondrial membrane potential (∆Ψm) is an indicator of mitochondrial activity and plays a major role in ATP production, redox balance, signaling and metabolism. Despite the absolute reliance of oocyte and early embryo development on mitochondrial function, there is little known about the spatial and temporal aspects of ΔΨm during oocyte maturation. The one exception is that previous findings using a ΔΨm indicator, JC-1, report that mitochondria in the cortex show a preferentially increased ΔΨm, relative to the rest of the cytoplasm. Using live-cell imaging and a new ratiometric approach for measuring ΔΨm in mouse oocytes, we find that ΔΨm increases through the time course of oocyte maturation and that mitochondria in the vicinity of the first meiotic spindle show an increase in ΔΨm, compared to other regions of the cytoplasm. We find no evidence for an elevated ΔΨm in the oocyte cortex. These findings suggest that mitochondrial activity is adaptive and responsive to the events of oocyte maturation at both a global and local level. In conclusion, we have provided a new approach to reliably measure ΔΨm that has shed new light onto the spatio-temporal regulation of mitochondrial function in oocytes and early embryos.

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Differential Effects of Silibinin A on Mitochondrial Function in Neuronal PC12 and HepG2 Liver Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/1652609 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 4

Author(s):

Carsten Esselun ◽

Bastian Bruns ◽

Stephanie Hagl ◽

Rekha Grewal ◽

Gunter P. Eckert

Keyword(s):

Membrane Potential ◽

Oxidative Phosphorylation ◽

Mitochondrial Membrane Potential ◽

Cell Lines ◽

Mitochondrial Function ◽

Mitochondrial Membrane ◽

Nitrosative Stress ◽

Citrate Synthase ◽

Atp Levels ◽

Age Related

The Mediterranean plant Silybum marianum L., commonly known as milk thistle, has been used for centuries to treat liver disorders. The flavonolignan silibinin represents a natural antioxidant and the main bioactive ingredient of silymarin (silybin), a standard extract of its seeds. Mitochondrial dysfunction and the associated generation of reactive oxygen/nitrogen species (ROS/RNS) are involved in the development of chronic liver and age-related neurodegenerative diseases. Silibinin A (SIL A) is one of two diastereomers found in silymarin and was used to evaluate the effects of silymarin on mitochondrial parameters including mitochondrial membrane potential and ATP production with and without sodium nitroprusside- (SNP-) induced nitrosative stress, oxidative phosphorylation, and citrate synthase activity in HepG2 and PC12 cells. Both cell lines were influenced by SIL A, but at different concentrations. SIL A significantly weakened nitrosative stress in both cell lines. Low concentrations not only maintained protective properties but also increased basal mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) levels. However, these effects could not be associated with oxidative phosphorylation. On the other side, high concentrations of SIL A significantly decreased MMP and ATP levels. Although SIL A did not provide a general improvement of the mitochondrial function, our findings show that SIL A protects against SNP-induced nitrosative stress at the level of mitochondria making it potentially beneficial against neurological disorders.

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Protective effect of the dimer of 16,16-diMePGB1 against KCN-induced mitochondrial failure in hepatocytes

AJP Cell Physiology ◽

10.1152/ajpcell.1992.263.2.c405 ◽

1992 ◽

Vol 263 (2) ◽

pp. C405-C411 ◽

Cited By ~ 11

Author(s):

Y. Park ◽

T. M. Devlin ◽

D. P. Jones

Keyword(s):

Membrane Potential ◽

Protective Effect ◽

Ion Transport ◽

Mitochondrial Membrane Potential ◽

Mitochondrial Function ◽

Mitochondrial Membrane ◽

Time Dependent ◽

Dependent Manner ◽

Protective Effects ◽

Cellular Swelling

The dimer and trimer of 16,16-dimethyl-15-dehydroprostaglandin B1 (16,16-diMePGB1) previously have been shown to have protective effects on mitochondrial function. To examine the potential mechanisms involved in protection against mitochondrial failure, we have studied the effects of the dimer of 16,16-diMe-PGB1 (dicalciphor) on mitochondrial function in hepatocytes exposed to KCN. Addition of micromolar concentrations of dicalciphor provided substantial protection against KCN-induced toxicity in a concentration- and time-dependent manner. Dicalciphor, however, had no effect on total or mitochondrial ATP losses in KCN-treated cells. The dimer prevented the marked loss of mitochondrial membrane potential (delta psi) and delta pH that occurs as a result of KCN treatment and prevented KCN-induced loading of phosphate in mitochondria. Furthermore, the dimer of 16,16-diMePGB1 also prevented KCN-induced mitochondrial and cellular swelling. These results demonstrate that dicalciphor protects against KCN-induced damage and that this protection is associated with regulation of specific mitochondrial ion transport functions.

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