Inhibition of mitochondrial oxidative metabolism by SKF-525a in intact cells and isolated mitochondria

In the present study, we have investigated gender differences in rat liver mitochondrial oxidative metabolism. Total mitochondrial population (M) as well as the heavy (M1), medium (M3), and light (M8) mitochondrial fractions obtained by means of differential centrifugation steps at 1,000, 3,000, and 8,000 g, respectively, were isolated. Electron microscopic analysis was performed and mitochondrial protein content and cardiolipin levels, mitochondrial O2 flux, ATP synthase activity, mitochondrial membrane potential, and mitochondrial transcription factor A (TFAM) protein levels were measured in each sample. Our results indicate that mitochondria from females have higher protein content and higher cardiolipin levels, greater respiratory and phosphorylative capacities, and more-energized mitochondria in respiratory state 3. Moreover, protein levels of TFAM were four times greater in females than in males. Gender differences in the aforementioned parameters were more patent in the isolated heavy M1 and M3 mitochondrial fractions. The present study demonstrates that gender-related differences in liver mitochondrial function are due mainly to a higher capacity and efficiency of substrate oxidation, likely related to greater mitochondrial machinery in females than in males, which is in accord with greater mitochondrial differentiation in females.

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The mitochondrial consequences of uncoupling intact cells depend on the nature of the exogenous substrate

Biochemical Journal ◽

10.1042/bj3550231 ◽

2001 ◽

Vol 355 (1) ◽

pp. 231-235 ◽

Cited By ~ 6

Author(s):

Brigitte SIBILLE ◽

Céline FILIPPI ◽

Marie-Astrid PIQUET ◽

Pascale LECLERCQ ◽

Eric FONTAINE ◽

...

Keyword(s):

Oxidation Rate ◽

Marked Decrease ◽

Electrical Potential ◽

Atp Synthesis ◽

Intact Cells ◽

Isolated Mitochondria ◽

Exogenous Substrate ◽

High Oxidation ◽

Transmembrane Electrical Potential ◽

Sustained Increase

In isolated mitochondria the consequences of oxidative phosphorylation uncoupling are well defined, whereas in intact cells various effects have been described. Uncoupling liver cells with 2,4-dinitrophenol (DNP) in the presence of dihydroxyacetone (DHA) and ethanol results in a marked decrease in mitochondrial transmembrane electrical potential (∆ψ), ATP/ADP ratios and gluconeogenesis (as an ATP-utilizing process), whereas the increased oxidation rate is limited and transient. Conversely, when DHA is associated with octanoate or proline, DNP addition results in a very large and sustained increase in oxidation rate, whereas the decreases in ∆ψ, ATP/ADP ratios and gluconeogenesis are significantly less when compared with DHA and ethanol. Hence significant energy wastage (high oxidation rate) by uncoupling is achieved only with substrates that are directly oxidized in the mitochondrial matrix. Conversely in the presence of substrates that are first oxidized in the cytosol, uncoupling results in a profound decrease in mitochondrial ∆ψ and ATP synthesis, whereas energy wastage is very limited.

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Mitochondrial oxidative metabolism contributes to a cancer stem cell phenotype in cholangiocarcinoma

Journal of Hepatology ◽

10.1016/j.jhep.2020.12.031 ◽

2021 ◽

Author(s):

Chiara Raggi ◽

Maria Letizia Taddei ◽

Elena Sacco ◽

Nadia Navari ◽

Margherita Correnti ◽

...

Keyword(s):

Stem Cell ◽

Cancer Stem Cell ◽

Oxidative Metabolism ◽

Cell Phenotype ◽

Cancer Stem Cell Phenotype ◽

Mitochondrial Oxidative Metabolism ◽

Stem Cell Phenotype

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Abstract P412: Mitochondrial Metabolic Transcriptome Profiles During Cardiomyocyte Differentiation From Mouse And Human Pluripotent Stem Cells

Circulation Research ◽

10.1161/res.129.suppl_1.p412 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Sung Woo Cho ◽

Hyoung Kyu Kim ◽

Jin Han ◽

Ji-Hee Sung

Keyword(s):

Stem Cells ◽

Pluripotent Stem Cells ◽

Oxidative Metabolism ◽

Time Dependent ◽

Lineage Commitment ◽

Simultaneous Increase ◽

Dependent Manner ◽

Cardiomyocyte Differentiation ◽

Cardiac Lineage ◽

Mitochondrial Oxidative Metabolism

Simultaneous increase of myofibrils and mitochondria is a key process of cardiomyocyte differentiation from pluripotent stem cells (PSCs). Specifically, development of mitochondrial oxidative energy metabolism in cardiomyocytes is essential to providing the beating function. Although previous studies reported that mitochondrial oxidative metabolism have some correlation with the differentiation of cardiomyocytes, the mechanism by which mitochondrial oxidative metabolism is regulated and the link between cardiomyogenesis and mitochondrial function are still poorly understood. In the present study, we performed transcriptome analysis on cells at specific stages of cardiomyocyte differentiation from mouse embryonic stem cells (mESCs) and human induced PSCs (hiPSCs). We selected highly upregulated mitochondrial metabolic genes at cardiac lineage commitment and time-dependent manner during cardiomyocyte differentiation and identified the protein-protein interaction network connecting between mitochondrial metabolic and cardiac developmental genes. We found several mitochondrial metabolic regulatory genes at cardiac lineage commitment (Cck, Bdnf, Fabp4, Cebpa, Cdkn2a in mESC-derived cells and CCK, NOS3 in hiPSC-derived cells) and time-dependent manner during cardiomyocyte differentiation (Eno3, Pgam2, Cox6a2, Fabp3 in mESC-derived cells and PGAM2, SLC25A4 in hiPSC-derived cells). Notably, mitochondrial metabolic proteins are highly interacted with cardiac developmental proteins time-dependent manner during cardiomyocyte differentiation rather than cardiac lineage commitment. Furthermore, mitochondrial metabolic proteins are mainly interacted with cardiac muscle contractile proteins rather than cardiac transcription factors in cardiomyocyte. Therefore, mitochondrial metabolism is critical at cardiac maturation rather than cardiac lineage commitment.

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Quercetin reduces obesity-induced hepatosteatosis by enhancing mitochondrial oxidative metabolism via heme oxygenase-1

Nutrition & Metabolism ◽

10.1186/s12986-015-0030-5 ◽

2015 ◽

Vol 12 (1) ◽

Cited By ~ 48

Author(s):

Chu-Sook Kim ◽

Yoonhee Kwon ◽

Suck-Young Choe ◽

Sun-Myung Hong ◽

Hoon Yoo ◽

...

Keyword(s):

Heme Oxygenase ◽

Oxidative Metabolism ◽

Heme Oxygenase 1 ◽

Mitochondrial Oxidative Metabolism

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Is the function of the renal papilla coupled exclusively to an anaerobic pattern of metabolism?

AJP Renal Physiology ◽

10.1152/ajprenal.1979.236.5.f423 ◽

1979 ◽

Vol 236 (5) ◽

pp. F423-F433 ◽

Cited By ~ 9

Author(s):

J. J. Cohen

Keyword(s):

Oxidative Metabolism ◽

Aerobic Glycolysis ◽

Collecting Duct ◽

High Rate ◽

O2 Uptake ◽

Duct Cells ◽

Collecting Duct Cells ◽

Mitochondrial Oxidative Metabolism

It is widely accepted that in vivo the function of the papilla of the mammalian kidney is supported primarily by anaerobic metabolism. As a result, the major source of energy for support of function in the papilla is considered to be derived from glycolysis. This orientation originates from two concepts: 1) that in vivo the gaseous environment of the papilla has such a low PO2 that O2 availability limits O2 consumption, and 2) that papillary tissue has a high rate of glycolysis when compared with either cortical tissue or extrarenal tissues. It has also been tacitly assumed that papillary tissue has a "low" O2 uptake. Review of the measurements of PO2 of papillary tissue and of urine PO2 indicates that the PO2 of papillary tissue should not limit its aerobic mitochondrial oxidative metabolism. While the rate of aerobic glycolysis in papillary tissue is high, simultaneously papillary tissue has a rate of O2 uptake similar to that of liver and higher than that of muscle. The major (two-thirds) source of energy for papillary tissue in vitro is from O2 uptake. That papillary tissue is not exclusively dependent on glucose for its energy requirements is indicated by the greater stimulation of papillary tissue QO2 by succinate than by glucose. Thus, papillary tissue has both a high aerobic mitochondrial oxidative metabolism and a high aerobic glycolytic metabolism. It is suggested that the mechanism for the high rate of aerobic glycolysis in the presence of an adequate O2 supply is due to the relatively small mass of mitochondria in papillary tissue in relation to the amount of work done by the tissue. As a result of the limited rate of ATP production by the mitochondrial electron transport chain, the phosphorylation state ([ATP]/[ADP][Pi]) is reduced and the cytoplasmic redox state ([NAD+]/[NADH]) of the papillary collecting duct cells also becomes more reduced; changes in both ratios enhance the rate of glycolysis. This limited metabolic capacity of the collecting duct cells may permit an excess volume of solute and water to be excreted during volume expansion diuresis. The metabolic characteristics of the papilla, when compared to cortex, also provide a basis for the observed differences in substrate selectivity of cortex and medulla with respect to utilization of glucose and lactate. The experimental approaches that may provide information bearing on the suggested mechanisms for regulation of papillary metabolism in relation to tubular work functions are indicated.

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TM4SF5 Knockout Protects Mice from Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue

10.2337/figshare.14831082.v1 ◽

2021 ◽

Author(s):

Cheoljun Choi ◽

Yeonho Son ◽

Jinyoung Kim ◽

Yoon Keun Cho ◽

Abhirup Saha ◽

...

Keyword(s):

Adipose Tissue ◽

Oxidative Metabolism ◽

Metabolic Diseases ◽

Mammalian Target Of Rapamycin ◽

Regulatory Function ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Brown Adipose ◽

Mtorc1 Signaling ◽

Mitochondrial Oxidative Metabolism

Transmembrane 4 L six family member 5 (TM4SF5) functions as a sensor for lysosomal arginine levels and activates the mammalian target of rapamycin complex 1 (mTORC1). While the mTORC1 signaling pathway plays a key role in adipose tissue metabolism, the regulatory function of TM4SF5 in adipocytes remains unclear. This study aimed to establish a TM4SF5 knockout (KO) mouse model and investigated the effects of TM4SF5 KO on mTORC1 signaling-mediated autophagy and mitochondrial metabolism in adipose tissue. TM4SF5 expression was higher in inguinal white adipose tissue (iWAT) than in brown adipose tissue and significantly upregulated by a high-fat diet (HFD). TM4SF5 KO reduced mTORC1 activation and enhanced autophagy and lipolysis in adipocytes. RNA-seq analysis of TM4SF5 KO mouse iWAT showed that the expression of genes involved in peroxisome proliferator-activated receptor alpha signaling pathways and mitochondrial oxidative metabolism was upregulated. Consequently, TM4SF5 KO reduced adiposity and increased energy expenditure and mitochondrial oxidative metabolism. TM4SF5 KO prevented HFD-induced glucose intolerance and inflammation in adipose tissue. Collectively, our study demonstrated that TM4SF5 regulates autophagy and lipid catabolism in adipose tissue and suggested that TM4SF5 could be therapeutically targeted for the treatment of obesity-related metabolic diseases.

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