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

Solesio, María E.; Xie, Lihan; McIntyre, Brendan; Ellenberger, Mathew; Mitaishvili, Erna; Bhadra-Lobo, Siddharth; Bettcher, Lisa; Bazil, Jason N.; Raftery, Daniel; Jakob, Ursula; Pavlov, Evgeny

doi:10.1042/bcj20200975

Cited by 31 publications

(31 citation statements)

References 61 publications

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“…Intrinsic to its polymeric charged nature is its ability to regulate phosphate and cation homeostasis. Additionally, polyP controls bacterial virulence [1], energy metabolism [2], protein folding [3], cell cycle progression [4], and signal transduction via lysine-polyphosphorylation [5]. This list of polyP-modulated functions is not exhaustive, and we recommend the interested readers the following polyP reviews [6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

The PPIP5K Family Member Asp1 Controls Inorganic Polyphosphate Metabolism in S. pombe

Pascual-Ortiz

Walla

Fleig

et al. 2021

JoF

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Inorganic polyphosphate (polyP) which is ubiquitously present in both prokaryotic and eukaryotic cells, consists of up to hundreds of orthophosphate residues linked by phosphoanhydride bonds. The biological role of this polymer is manifold and diverse and in fungi ranges from cell cycle control, phosphate homeostasis and virulence to post-translational protein modification. Control of polyP metabolism has been studied extensively in the budding yeast Saccharomyces cerevisiae. In this yeast, a specific class of inositol pyrophosphates (IPPs), named IP7, made by the IP6K family member Kcs1 regulate polyP synthesis by associating with the SPX domains of the vacuolar transporter chaperone (VTC) complex. To assess if this type of regulation was evolutionarily conserved, we determined the elements regulating polyP generation in the distantly related fission yeast Schizosaccharomyces pombe. Here, the VTC machinery is also essential for polyP generation. However, and in contrast to S. cerevisiae, a different IPP class generated by the bifunctional PPIP5K family member Asp1 control polyP metabolism. The analysis of Asp1 variant S. pombe strains revealed that cellular polyP levels directly correlate with Asp1-made IP8 levels, demonstrating a dose-dependent regulation. Thus, while the mechanism of polyP synthesis in yeasts is conserved, the IPP player regulating polyP metabolism is diverse.

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Section: Introductionmentioning

confidence: 99%

The PPIP5K Family Member Asp1 Controls Inorganic Polyphosphate Metabolism in S. pombe

Pascual-Ortiz

Walla

Fleig

et al. 2021

JoF

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“…While mitochondrial-free calcium homeostasis still remains poorly understood, it has been proposed that inorganic polyphosphate (polyP) could play a key role in this process [ 137 , 138 ]. 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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“…Interestingly, ROS are closely related to high energy phosphates in mitochondrial, as they are both produced during OXPHOS. One important source of high energy phosphate inside mitochondria is inorganic polyphosphate (polyP) [ 29 , 30 , 31 , 31 ]. In fact, the involvement of polyP on heart physiology, has been already demonstrated in cardiac myocytes [ 32 , 33 , 34 ].…”

Section: Aldosterone and Mitochondrial Dysfunction In The Failing Heartmentioning

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

Cited by 31 publications

References 61 publications

The PPIP5K Family Member Asp1 Controls Inorganic Polyphosphate Metabolism in S. pombe

The PPIP5K Family Member Asp1 Controls Inorganic Polyphosphate Metabolism in S. pombe

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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