Mitochondrial localization of NCXs: Balancing calcium and energy homeostasis

Magi, Simona; Piccirillo, Silvia; Preziuso, Alessandra; Amoroso, Salvatore; Lariccia, Vincenzo

doi:10.1016/j.ceca.2020.102162

Cited by 20 publications

(8 citation statements)

References 129 publications

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“…In line with this observation, in control conditions, glutamate can induce a slight but significant increase in both cytosolic and mitochondrial Ca 2+ levels ( Figure 5), consistently with our previous findings [38,41] and as already proposed in astrocytes [87,88]. The latter event activates the mitochondrial Ca 2+ sensitive dehydrogenases, driving glutamate utilization and enhancing ATP synthesis [50]. It is worth noting that both Ca 2+ and glutamate are essential to promote the synthesis of ATP [38].…”

Section: Discussionsupporting

confidence: 91%

“…Three NCX isoforms have been identified, namely NCX1, NCX2 and NCX3, which are expressed in a tissue-specific manner [45][46][47][48][49]. In this regard, we have previously demonstrated a physical and functional interaction between a specific EAATs subtype, EAAT3 (excitatory amino acid carrier 1, EAAC1 in rodents) and NCX1 at both the plasma membrane and the mitochondrial levels [38,41,50]. In both cardiac and neuronal models, their interaction modulates the glutamate-driven ATP synthesis under pathophysiological conditions [38][39][40][41]51].…”

Section: Introductionmentioning

confidence: 98%

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Gateways for Glutamate Neuroprotection in Parkinson’s Disease (PD): Essential Role of EAAT3 and NCX1 Revealed in an In Vitro Model of PD

Piccirillo

Magi

Preziuso

et al. 2020

Cells

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Increasing evidence suggests that metabolic alterations may be etiologically linked to neurodegenerative disorders such as Parkinson’s disease (PD) and in particular empathizes the possibility of targeting mitochondrial dysfunctions to improve PD progression. Under different pathological conditions (i.e., cardiac and neuronal ischemia/reperfusion injury), we showed that supplementation of energetic substrates like glutamate exerts a protective role by preserving mitochondrial functions and enhancing ATP synthesis through a mechanism involving the Na+-dependent excitatory amino acid transporters (EAATs) and the Na+/Ca2+ exchanger (NCX). In this study, we investigated whether a similar approach aimed at promoting glutamate metabolism would be also beneficial against cell damage in an in vitro PD-like model. In retinoic acid (RA)-differentiated SH-SY5Y cells challenged with α-synuclein (α-syn) plus rotenone (Rot), glutamate significantly improved cell viability by increasing ATP levels, reducing oxidative damage and cytosolic and mitochondrial Ca2+ overload. Glutamate benefits were strikingly lost when either EAAT3 or NCX1 expression was knocked down by RNA silencing. Overall, our results open the possibility of targeting EAAT3/NCX1 functions to limit PD pathology by simultaneously favoring glutamate uptake and metabolic use in dopaminergic neurons.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 98%

Gateways for Glutamate Neuroprotection in Parkinson’s Disease (PD): Essential Role of EAAT3 and NCX1 Revealed in an In Vitro Model of PD

Piccirillo

Magi

Preziuso

et al. 2020

Cells

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“…Only when MAMs and mitochondria–lysosome contacts are stable can Ca 2+ transport maintain homeostasis. Ca 2+ transport homeostasis is beneficial for material transport and energy metabolism [ 148 ].…”

Section: Discussionmentioning

confidence: 99%

The pathological role of damaged organelles in renal tubular epithelial cells in the progression of acute kidney injury

Liu

Luo

et al. 2022

Cell Death Discov.

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Acute kidney injury (AKI) is a common clinical condition associated with high morbidity and mortality. The pathogenesis of AKI has not been fully elucidated, with a lack of effective treatment. Renal tubular epithelial cells (TECs) play an important role in AKI, and their damage and repair largely determine the progression and prognosis of AKI. In recent decades, it has been found that the mitochondria, endoplasmic reticulum (ER), lysosomes, and other organelles in TECs are damaged to varying degrees in AKI, and that they can influence each other through various signaling mechanisms that affect the recovery of TECs. However, the association between these multifaceted signaling platforms, particularly between mitochondria and lysosomes during AKI remains unclear. This review summarizes the specific pathophysiological mechanisms of the main TECs organelles in the context of AKI, particularly the potential interactions among them, in order to provide insights into possible novel treatment strategies.

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“…For example, in recent years some data were obtained indicating that the mitochondrial membrane contains calcium channels, similar to receptor‐related ion channels of the plasmatic membrane. It was shown that the sodium–calcium exchanger isoforms of the plasmatic membrane (NCX) are also expressed in mitochondria 159 . The 5‐HTR3 and 5‐HTR4 subtype serotonin receptors can also be located in the mitochondrial membrane and their ligands inhibit the MPT process 160 …”

Section: Mitochondria As a Essential Target For Multitarget Neuroactimentioning

confidence: 99%

Mitochondria as a promising target for developing novel agents for treating Alzheimer's disease

Shevtsova

Maltsev

Vinogradova

et al. 2020

Medicinal Research Reviews

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The mitochondria‐targeting drugs can be conventionally divided into the following groups: those compensating for the energy deficit involved in neurodegeneration, including stimulants of mitochondrial bioenergetics and activators of mitochondrial biogenesis; and neuroprotectors, that are compounds increasing the resistance of mitochondria to opening of mitochondrial permeability transition (MPT) pores. Although compensating for the energy deficit and inhibition of MPT are obvious targets for drugs used in the very early stages of Alzheimer‐like pathology, but their use as the monotherapy for patients with severe symptoms is unlikely to be sufficiently effective. It would be optimal to combine targets that would provide the cognitive‐stimulating, the neuroprotective effects and the ability to affect specific disease‐forming mechanisms. In the design of such drugs, assessment of their potential mitochondrial‐targeted effects is of particular importance. The possibility of targeted drug design for simultaneous action on mitochondrial and neurotransmitter's receptors targets is, in particularly, based on the known interplay of various cellular pathways and the presence of common structural components. Of particular interest is directed search for multitarget drugs that would act simultaneously on mitochondrial calcium‐dependent functions, the targets (receptors, enzymes, etc.) facilitating neurotransmission, and the molecular targets related to the action of so‐called disease‐modifying factors, in particular, the formation and overcoming of the toxicity of β‐amyloid or hyperphosphorylated tau protein. The examples of such approaches realized on the level of preclinical and clinical trials are presented below.

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Mitochondrial localization of NCXs: Balancing calcium and energy homeostasis

Cited by 20 publications

References 129 publications

Gateways for Glutamate Neuroprotection in Parkinson’s Disease (PD): Essential Role of EAAT3 and NCX1 Revealed in an In Vitro Model of PD

Gateways for Glutamate Neuroprotection in Parkinson’s Disease (PD): Essential Role of EAAT3 and NCX1 Revealed in an In Vitro Model of PD

The pathological role of damaged organelles in renal tubular epithelial cells in the progression of acute kidney injury

Mitochondria as a promising target for developing novel agents for treating Alzheimer's disease

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