scholarly journals Depletion of mitochondrial inorganic polyphosphate (polyP) in mammalian cells causes metabolic shift from oxidative phosphorylation to glycolysis.

2021 ◽  
Author(s):  
Maria E. Solesio ◽  
Lihan Xie ◽  
Brendan McIntyre ◽  
Mathew Ellenberger ◽  
Erna Mitaishvili ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Oxidative Phosphorylation ◽  
Mammalian Cells ◽  
High Energy ◽  
Hek293 Cells ◽  
Wild Type ◽  
Inorganic Polyphosphate ◽  
Metabolic Switch ◽  
Respiratory Parameters ◽  
Respiratory Chain Activity

Inorganic polyphosphate (polyP) is a linear polymer composed of up to a few hundred orthophosphates linked together by high-energy phosphoanhydride bonds, identical to those found in ATP. In mammalian mitochondria, polyP has been implicated in multiple processes, including energy metabolism, ion channels function, and the regulation of calcium signaling. However, the specific mechanisms of all these effects of polyP within the organelle remain poorly understood. The central goal of this study was to investigate how mitochondrial polyP participates in the regulation of the mammalian cellular energy metabolism. To accomplish this, we created HEK293 cells depleted of mitochondrial polyP, through the stable expression of the polyP hydrolyzing enzyme (scPPX). We found that these cells have significantly reduced rates of oxidative phosphorylation (OXPHOS), while their rates of glycolysis were elevated. Consistent with this, metabolomics assays confirmed increased levels of metabolites involved in glycolysis in these cells, compared with the wild-type samples. At the same time, key respiratory parameters of the isolated mitochondria were unchanged, suggesting that respiratory chain activity is not affected by the lack of mitochondrial polyP. However, we detected that mitochondria from cells that lack mitochondrial polyP are more fragmented when compared with those from wild-type cells. Based on these results, we propose that mitochondrial polyP plays an important role as a regulator of the metabolic switch between OXPHOS and glycolysis.

scholarly journals Wild-Type p53 Promotes Cancer Metabolic Switch by Inducing PUMA-Dependent Suppression of Oxidative Phosphorylation

Cancer Cell ◽  
2019 ◽  
Vol 35 (2) ◽  
pp. 191-203.e8 ◽  
Author(s):  
Jinchul Kim ◽  
Lili Yu ◽  
Wancheng Chen ◽  
Yanxia Xu ◽  
Meng Wu ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Wild Type ◽  
Metabolic Switch ◽  
Wild Type P53

scholarly journals Inorganic Polyphosphate and Energy Metabolism in Mammalian Cells

2010 ◽  
Vol 285 (13) ◽  
pp. 9420-9428 ◽  
Author(s):  
Evgeny Pavlov ◽  
Roozbeh Aschar-Sobbi ◽  
Michelangelo Campanella ◽  
Raymond J. Turner ◽  
María R. Gómez-García ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Mammalian Cells ◽  
Inorganic Polyphosphate

scholarly journals Rescue of Volume-regulated Anion Current by Bestrophin Mutants with Altered Charge Selectivity

2008 ◽  
Vol 132 (5) ◽  
pp. 537-546 ◽  
Author(s):  
Li-Ting Chien ◽  
H. Criss Hartzell
Keyword(s):  
Mammalian Cells ◽  
Anion Channel ◽  
Peritoneal Macrophages ◽  
Hek293 Cells ◽  
S2 Cells ◽  
Wild Type ◽  
Biophysical Properties ◽  
Ionic Selectivity ◽  
Charge Selectivity ◽  
Cl Channels

Mutations in human bestrophin-1 are linked to various kinds of retinal degeneration. Although it has been proposed that bestrophins are Ca2+-activated Cl− channels, definitive proof is lacking partly because mice with the bestrophin-1 gene deleted have normal Ca2+-activated Cl− currents. Here, we provide compelling evidence to support the idea that bestrophin-1 is the pore-forming subunit of a cell volume-regulated anion channel (VRAC) in Drosophila S2 cells. VRAC was abolished by treatment with RNAi to Drosophila bestrophin-1. VRAC was rescued by overexpressing bestrophin-1 mutants with altered biophysical properties and responsiveness to sulfhydryl reagents. In particular, the ionic selectivity of the F81C mutant changed from anionic to cationic when the channel was treated with the sulfhydryl reagent, sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES−) (PCs/PCl = 0.25 for native and 2.38 for F81C). The F81E mutant was 1.3 times more permeable to Cs+ than Cl−. The finding that VRAC was rescued by F81C and F81E mutants with different biophysical properties shows that bestrophin-1 is a VRAC in S2 cells and not simply a regulator or an auxiliary subunit. F81C overexpressed in HEK293 cells also exhibits a shift of ionic selectivity after MTSES− treatment, although the effect is quantitatively smaller than in S2 cells. To test whether bestrophins are VRACs in mammalian cells, we compared VRACs in peritoneal macrophages from wild-type mice and mice with both bestrophin-1 and bestrophin-2 disrupted (best1−/−/best2−/−). VRACs were identical in wild-type and best1−/−/best2−/− mice, showing that bestrophins are unlikely to be the classical VRAC in mammalian cells.

Mitochondrial cytochrome c oxidase and control of energy metabolism: measurements in suspensions of isolated mitochondria

2014 ◽  
Vol 117 (12) ◽  
pp. 1424-1430 ◽  
Author(s):  
David F. Wilson ◽  
David K. Harrison ◽  
Andrei Vinogradov
Keyword(s):  
Oxygen Consumption ◽  
Energy Metabolism ◽  
Cytochrome C ◽  
Oxidative Phosphorylation ◽  
Respiratory Rate ◽  
Cytochrome C Oxidase ◽  
Energy State ◽  
Atp Synthesis ◽  
Oxygen Depletion ◽  
High Energy

Cytochrome c oxidase is the enzyme responsible for oxygen consumption by mitochondrial oxidative phosphorylation and coupling site 3 of oxidative phosphorylation. In this role it determines the cellular rate of ATP synthesis by oxidative phosphorylation and is the key to understanding how energy metabolism is regulated. Four electrons are required for the reduction of oxygen to water, and these are provided by the one-electron donor, cytochrome c. The rate of oxygen consumption (ATP synthesis) is dependent on the fraction of cytochrome c reduced (fred), oxygen pressure (pO2), energy state ([ATP]/[ADP][Pi]), and pH. In coupled mitochondria (high energy state) and pO2 >60 torr, the rate increases in an exponential-like fashion with increasing fred. When the dependence on fred is fitted to the equation rate = a(fred)b, a decreased from 100 to near 20, and b increased from 1.3 to 4 as the pH of the medium increased from 6.5 to 8.3. During oxygen depletion from the medium fred progressively increases and the rate of respiration decreases. The respiratory rate falls to ½ (P50) by about 1.5 torr, at which point fred is substantially increased. The metabolically relevant dependence on pO2 is obtained by correcting for the increase in fred, in which case the P50 is 12 torr. Adding an uncoupler of oxidative phosphorylation eliminates the dependence of the cytochrome c oxidase activity on pH and energy state. The respiratory rate becomes proportional to fred and the P50 decreases to less than 1 torr.

scholarly journals Inorganic polyphosphate in mammals: where's Wally?

2020 ◽  
Vol 48 (1) ◽  
pp. 95-101 ◽  
Author(s):  
Yann Desfougères ◽  
Adolfo Saiardi ◽  
Cristina Azevedo
Keyword(s):  
Mammalian Cells ◽  
Biosynthetic Pathway ◽  
High Energy ◽  
Detection Methods ◽  
Polyp Detection ◽  
Inorganic Polyphosphate ◽  
Mammalian Enzyme ◽  
Higher Eukaryotes ◽  
Low Sensitivity ◽  
Current Detection

Inorganic polyphosphate (polyP) is a ubiquitous polymer of tens to hundreds of orthophosphate residues linked by high-energy phosphoanhydride bonds. In prokaryotes and lower eukaryotes, both the presence of polyP and of the biosynthetic pathway that leads to its synthesis are well-documented. However, in mammals, polyP is more elusive. Firstly, the mammalian enzyme responsible for the synthesis of this linear biopolymer is unknown. Secondly, the low sensitivity and specificity of available polyP detection methods make it difficult to confidently ascertain polyP presence in mammalian cells, since in higher eukaryotes, polyP exists in lower amounts than in yeast or bacteria. Despite this, polyP has been given a remarkably large number of functions in mammals. In this review, we discuss some of the proposed functions of polyP in mammals, the limitations of the current detection methods and the urgent need to understand how this polymer is synthesized.

scholarly journals Role of Inositols and Inositol Phosphates in Energy Metabolism

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5079 ◽  
Author(s):  
Saimai Chatree ◽  
Nanthaphop Thongmaen ◽  
Kwanchanit Tantivejkul ◽  
Chantacha Sitticharoon ◽  
Ivana Vucenik
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Energy Metabolism ◽  
Mammalian Cells ◽  
Inositol Phosphates ◽  
Inositol Phosphate ◽  
Biological Activities ◽  
High Energy ◽  
Beneficial Effects ◽  
Treatment And Prevention

Recently, inositols, especially myo-inositol and inositol hexakisphosphate, also known as phytic acid or IP6, with their biological activities received much attention for their role in multiple health beneficial effects. Although their roles in cancer treatment and prevention have been extensively reported, interestingly, they may also have distinctive properties in energy metabolism and metabolic disorders. We review inositols and inositol phosphate metabolism in mammalian cells to establish their biological activities and highlight their potential roles in energy metabolism. These molecules are known to decrease insulin resistance, increase insulin sensitivity, and have diverse properties with importance from cell signaling to metabolism. Evidence showed that inositol phosphates might enhance the browning of white adipocytes and directly improve insulin sensitivity through adipocytes. In addition, inositol pyrophosphates containing high-energy phosphate bonds are considered in increasing cellular energetics. Despite all recent advances, many aspects of the bioactivity of inositol phosphates are still not clear, especially their effects on insulin resistance and alteration of metabolism, so more research is needed.

Role of inorganic polyphosphate in mammalian cells: from signal transduction and mitochondrial metabolism to cell death

2016 ◽  
Vol 44 (1) ◽  
pp. 40-45 ◽  
Author(s):  
Plamena R. Angelova ◽  
Artyom Y. Baev ◽  
Alexey V. Berezhnov ◽  
Andrey Y. Abramov
Keyword(s):  
Signal Transduction ◽  
Cell Death ◽  
Mammalian Cells ◽  
High Energy ◽  
Mitochondrial Metabolism ◽  
Calcium Handling ◽  
Calcium Signal ◽  
Inorganic Polyphosphate ◽  
Long Chain

Inorganic polyphosphate (polyP) is a polymer compromised of linearly arranged orthophosphate units that are linked through high-energy phosphoanhydride bonds. The chain length of this polymer varies from five to several thousand orthophosphates. PolyP is distributed in the most of the living organisms and plays multiple functions in mammalian cells, it is important for blood coagulation, cancer, calcium precipitation, immune response and many others. Essential role of polyP is shown for mitochondria, from implication into energy metabolism and mitochondrial calcium handling to activation of permeability transition pore (PTP) and cell death. PolyP is a gliotransmitter which transmits the signal in astrocytes via activation of P2Y1 receptors and stimulation of phospholipase C. PolyP-induced calcium signal in astrocytes can be stimulated by different lengths of this polymer but only long chain polyP induces mitochondrial depolarization by inhibition of respiration and opening of the PTP. It leads to induction of astrocytic cell death which can be prevented by inhibition of PTP with cyclosporine A. Thus, medium- and short-length polyP plays role in signal transduction and mitochondrial metabolism of astrocytes and long chain of this polymer can be toxic for the cells.

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