Is there a link between inorganic polyphosphate (polyP), mitochondria, and neurodegeneration?

Borden, Emily A.; Furey, Matthew J.; Gattone, Nicholas J.; Hambardikar, Vedangi D.; Liang, Xiao; Scoma, Ernest R.; Samra, Antonella Abou; D-Gary, LaKeshia R.; Dennis, Dayshaun J.; Fricker, Daniel; Garcia, Cindy; Jiang, ZeCheng; Khan, Shazia; Kumarasamy, Dheenadhayalan; Kuppala, Hasmitha; Ringrose, Savannah; Rosenheim, Evan J.; Exel, Kimberly Van; Vudhayagiri, Hemanth Sai; Zhang, Jiarui; Zhang, Zhaowen; Guitart‐Mampel, Mariona; Urquiza, Pedro; Solesio, María E.

doi:10.1016/j.phrs.2020.105211

Cited by 23 publications

(21 citation statements)

References 175 publications

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“…PolyP, which bounds are isoenergetic to those found in ATP (4), has been proposed to play a crucial role in cellular energy storage, allowing for the stored energy to be easily available under conditions of cellular stress (5,6). In fact, the role of this polymer as a key energy metabolite has already been demonstrated in a wide-variety of organisms and models (2,3,(7)(8)(9)(10)(11)(12)(13)(14). Consistent with its high energy feature and its preferred mitochondrial localization, polyP was recently proposed of being produced and hydrolyzed by the mammalian mitochondrial ATP synthase (15).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, accumulation of polyP has also found to play a key role in the energy metabolism of Dictyostelium discouideum, which show a 2.5-fold decrease in their ATP levels when the polyphosphate synthesizing enzyme PPK1 is deleted (17). In addition to its potentially direct involvement into cellular energy metabolism, mitochondrial polyP has also been implied in the regulation of the mitochondrial permeability transition pore (mPTP) (18)(19)(20)(21) and in the buffering of mitochondrial calcium (3,7,14). Both mPTP and mitochondrial calcium homeostasis are closely related to the bioenergetic status of the cells.…”

Section: Introductionmentioning

confidence: 99%

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

Solesio

Xie

McIntyre

et al. 2021

Biochemical Journal

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Solesio

Xie

McIntyre

et al. 2021

Biochemical Journal

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“…Interestingly, polyP has also been demonstrated to be crucial in mammalian bioenergetics [ 47 ], including the regulation of the mPTP [ 65 , 139 ], as well as in the physiology of the endoplasmic reticulum (ER) [ 140 ]. Furthermore, this polymer has also been proposed to have a protective role in neurodegenerative disorders, including AD [ 48 , 49 ].…”

Section: Mitochondrial Calcium Homeostasismentioning

confidence: 99%

“…One of the main components of mitochondrial physiology is the maintenance of an appropriate bioenergetics status. Accordingly, dysregulated bioenergetics is well described in AD [ 46 , 47 , 48 , 49 ]. While extra-mitochondrial pathways are also involved in mammalian cellular bioenergetics, the main source of ATP in these organisms is mitochondrial oxidative phosphorylation (OXPHOS) [ 50 ].…”

Section: Introductionmentioning

confidence: 99%

ATP Synthase and Mitochondrial Bioenergetics Dysfunction in Alzheimer’s Disease

Patro

Ratna

Yamamoto

et al. 2021

IJMS

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Alzheimer’s Disease (AD) is the most common neurodegenerative disorder in our society, as the population ages, its incidence is expected to increase in the coming decades. The etiopathology of this disease still remains largely unclear, probably because of the highly complex and multifactorial nature of AD. However, the presence of mitochondrial dysfunction has been broadly described in AD neurons and other cellular populations within the brain, in a wide variety of models and organisms, including post-mortem humans. Mitochondria are complex organelles that play a crucial role in a wide range of cellular processes, including bioenergetics. In fact, in mammals, including humans, the main source of cellular ATP is the oxidative phosphorylation (OXPHOS), a process that occurs in the mitochondrial electron transfer chain (ETC). The last enzyme of the ETC, and therefore the ulterior generator of ATP, is the ATP synthase. Interestingly, in mammalian cells, the ATP synthase can also degrade ATP under certain conditions (ATPase), which further illustrates the crucial role of this enzyme in the regulation of cellular bioenergetics and metabolism. In this collaborative review, we aim to summarize the knowledge of the presence of dysregulated ATP synthase, and of other components of mammalian mitochondrial bioenergetics, as an early event in AD. This dysregulation can act as a trigger of the dysfunction of the organelle, which is a clear component in the etiopathology of AD. Consequently, the pharmacological modulation of the ATP synthase could be a potential strategy to prevent mitochondrial dysfunction in AD.

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“…At the cellular level, mitochondrial dysfunction has been described as a crucial component of the etiopathology of multiple diseases [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ], including cardiac dysfunction induced by elevated aldosterone [ 15 ]. Moreover, it is known that aldosterone increases the production of reactive oxygen species (ROS), via NADPH oxidase [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function

Guitart‐Mampel

Urquiza

Borges

et al. 2021

Cells

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The mineralocorticoid aldosterone regulates electrolyte and blood volume homeostasis, but it also adversely modulates the structure and function of the chronically failing heart, through its elevated production in chronic human post-myocardial infarction (MI) heart failure (HF). By activating the mineralocorticoid receptor (MR), a ligand-regulated transcription factor, aldosterone promotes inflammation and fibrosis of the heart, while increasing oxidative stress, ultimately induding mitochondrial dysfunction in the failing myocardium. To reduce morbidity and mortality in advanced stage HF, MR antagonist drugs, such as spironolactone and eplerenone, are used. In addition to the MR, aldosterone can bind and stimulate other receptors, such as the plasma membrane-residing G protein-coupled estrogen receptor (GPER), further complicating it signaling properties in the myocardium. Given the salient role that adrenergic receptor (ARs)—particularly βARs—play in cardiac physiology and pathology, unsurprisingly, that part of the impact of aldosterone on the failing heart is mediated by its effects on the signaling and function of these receptors. Aldosterone can significantly precipitate the well-documented derangement of cardiac AR signaling and impairment of AR function, critically underlying chronic human HF. One of the main consequences of HF in mammalian models at the cellular level is the presence of mitochondrial dysfunction. As such, preventing mitochondrial dysfunction could be a valid pharmacological target in this condition. This review summarizes the current experimental evidence for this aldosterone/AR crosstalk in both the healthy and failing heart, and the impact of mitochondrial dysfunction in HF. Recent findings from signaling studies focusing on MR and AR crosstalk via non-conventional signaling of molecules that normally terminate the signaling of ARs in the heart, i.e., the G protein-coupled receptor-kinases (GRKs), are also highlighted.

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Is there a link between inorganic polyphosphate (polyP), mitochondria, and neurodegeneration?

Cited by 23 publications

References 175 publications

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

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

ATP Synthase and Mitochondrial Bioenergetics Dysfunction in Alzheimer’s Disease

Impact of Aldosterone on the Failing Myocardium: Insights from Mitochondria and Adrenergic Receptors Signaling and Function

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