Mitochondrial Ca
            <sup>2+</sup>
            transport in the endothelium: regulation by ions, redox signalling and mechanical forces

Alevriadou, B. Rita; Shanmughapriya, Santhanam; Patel, Abhishek; Stathopulos, Peter B.; Madesh, Muniswamy

doi:10.1098/rsif.2017.0672

Cited by 29 publications

(16 citation statements)

References 206 publications

(325 reference statements)

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“…Along with the ER, mitochondria also play important roles in calcium homeostasis and signaling [ 38 ]. Given the connections between Vps45 and mitochondrial function established above and known connections with calcium homeostasis in yeast [ 35 ], we next tested our strains for their susceptibility to calcium inhibitors.…”

Section: Resultsmentioning

confidence: 99%

The Sec1/Munc18 (SM) protein Vps45 is involved in iron uptake, mitochondrial function and virulence in the pathogenic fungus Cryptococcus neoformans

Caza

Nielson

et al. 2018

PLoS Pathog

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The battle for iron between invading microorganisms and mammalian hosts is a pivotal determinant of the outcome of infection. The pathogenic fungus, Cryptococcus neoformans, employs multiple mechanisms to compete for iron during cryptococcosis, a disease primarily of immunocompromised hosts. In this study, we examined the role of endocytic trafficking in iron uptake by characterizing a mutant defective in the Sec1/Munc18 (SM) protein Vps45. This protein is known to regulate the machinery for vesicle trafficking and fusion via interactions with SNARE proteins. As expected, a vps45 deletion mutant was impaired in endocytosis and showed sensitivity to trafficking inhibitors. The mutant also showed poor growth on iron-limited media and a defect in transporting the Cfo1 ferroxidase of the high-affinity iron uptake system from the plasma membrane to the vacuole. Remarkably, we made the novel observation that Vps45 also contributes to mitochondrial function in that a Vps45-Gfp fusion protein associated with mitotracker, and a vps45 mutant showed enhanced sensitivity to inhibitors of electron transport complexes as well as changes in mitochondrial membrane potential. Consistent with mitochondrial function, the vps45 mutant was impaired in calcium homeostasis. To assess the relevance of these defects for virulence, we examined cell surface properties of the vps45 mutant and found increased sensitivity to agents that challenge cell wall integrity and to antifungal drugs. A change in cell wall properties was consistent with our observation of altered capsule polysaccharide attachment, and with attenuated virulence in a mouse model of cryptococcosis. Overall, our studies reveal a novel role for Vps45-mediated trafficking for iron uptake, mitochondrial function and virulence.

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Section: Resultsmentioning

confidence: 99%

The Sec1/Munc18 (SM) protein Vps45 is involved in iron uptake, mitochondrial function and virulence in the pathogenic fungus Cryptococcus neoformans

Caza

Nielson

et al. 2018

PLoS Pathog

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“…These increased ROS and Ca 2+ affect mitochondrial ATP generation by modulating the activity of the electron transport chain and ATP synthase, whereas the produced ATP influences ROS production and Ca 2+ concentration. These mutual interplays among ROS, Ca 2+ , and ATP are thought to play an important role in maintaining EC homeostasis (1, 10). In the present study, we examined whether Ca 2+ and ROS are involved in shear stress-induced mitochondrial ATP production and ATP release.…”

Section: Discussionmentioning

confidence: 99%

Shear stress augments mitochondrial ATP generation that triggers ATP release and Ca²⁺signaling in vascular endothelial cells

Yamamoto

Imamura

Ando

2018

American Journal of Physiology-Heart and Circulatory Physiology

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Vascular endothelial cells (ECs) sense and transduce hemodynamic shear stress into intracellular biochemical signals, and Ca signaling plays a critical role in this mechanotransduction, i.e., the ECs release ATP in the caveolae in response to shear stress, and in turn, the released ATP activates the P2 purinoceptors, which results in an influx into the cells of extracellular Ca. However, the mechanism by which the shear stress evokes ATP release remains unclear. Here we demonstrate that the cellular mitochondria play a critical role in this process. Cultured human pulmonary artery ECs were exposed to controlled levels of shear stress in a flow-loading device and the changes in the mitochondrial ATP levels were examined by real-time imaging using a fluorescence resonance energy transfer-based ATP biosensor. Immediately upon the exposure of the cells to flow, the mitochondrial ATP levels increased, which was both reversible and dependent on the shear stress intensity. Inhibitors of the mitochondrial electron transport chain and ATP synthase, as well as knockdown of caveolin-1, a major structural protein of the caveolae, abolished the shear-stress-induced mitochondrial ATP generation, resulting in the loss of the ATP release and influx of Ca into the cells. These results suggest the novel role of the mitochondria in transducing the shear stress into ATP generation: the ATP generation leads to ATP release in the caveolae, triggering purinergic Ca signaling. Thus, exposure of ECs to shear stress seems to activate mitochondrial ATP generation through caveola- or caveolin-1-mediated mechanisms.

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“…EMRE is a necessary regulatory protein for MCU. The inhibition of EMRE will reduce the activity of MCU, which can interact with MCU, as well as MICU1 and MICU2 (Alevriadou et al, 2017; Penna et al, 2018). As the core channel of the MCU complex, MCU can mediate Ca 2+ transport and participate in the regulation of ATP production (Zaglia et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Salsolinol Attenuates Doxorubicin-Induced Chronic Heart Failure in Rats and Improves Mitochondrial Function in H9c2 Cardiomyocytes

et al. 2019

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Backgrounds: Salsolinol (SAL), a plant-based isoquinoline alkaloid, was initially isolated from Aconiti Lateralis Radix Praeparata (ALRP) and identified as the active cardiotonic component of ALRP. This study was aimed to explore the therapeutic effect and mechanism by which SAL attenuates doxorubicin (DOX)-induced chronic heart failure (CHF) in rats and improves mitochondrial function in H9c2 cardiomyocytes. Methods: Rats were intraperitoneally injected with DOX to establish CHF model. Therapeutic effects of SAL on hemodynamic parameters, serum indices, and the histopathology of the heart were analyzed in vivo. Moreover, H9c2 cardiomyocytes were pretreated with SAL for 2 h before DOX treatment in all procedures in vitro. Cell viability, cardiomyocyte morphology, proliferation, and mitochondrial function were detected by a high-content screening (HCS) assay. In addition, a Seahorse Extracellular Flux (XFp) analyzer was used to evaluate the cell energy respiratory and energy metabolism function. To further investigate the potential mechanism of SAL, relative mRNA and protein expression of key enzymes in the tricarboxylic acid cycle in vivo and mitochondrial calcium uniporter (MCU) signaling pathway-related molecules in vitro were detected. Results: The present data demonstrated the pharmacological effect of SAL on DOX-induced CHF, which was through ameliorating heart function, downregulating serum levels of myocardial injury markers, alleviating histological injury to the heart, increasing the relative mRNA expression levels of key enzymes downstream of the tricarboxylic acid cycle in vivo, and thus enhancing myocardial energy metabolism. In addition, SAL had effects on increasing cell viability, ameliorating DOX-induced mitochondrial dysfunction, and increasing mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in H9c2 cardiomyocyte. Moreover, we found that SAL might have an effect on improving mitochondrial respiratory function and energy metabolism via inhibiting excessive activation of MCU pathway in H9c2 cells. However, the protective effect could be ameliorated by ruthenium red (an MCU inhibitor) and abrogated by spermine (an MCU activator) in vitro. Conclusion: The therapeutic effects of SAL on CHF are possibly related to ameliorating cardiomyocyte function resulting in promotion of mitochondrial respiratory and energy metabolism. Furthermore, the potential mechanism might be related to downregulating MCU pathway. These findings may provide a potential therapy for CHF.

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Mitochondrial Ca ²⁺ transport in the endothelium: regulation by ions, redox signalling and mechanical forces

Cited by 29 publications

References 206 publications

The Sec1/Munc18 (SM) protein Vps45 is involved in iron uptake, mitochondrial function and virulence in the pathogenic fungus Cryptococcus neoformans

The Sec1/Munc18 (SM) protein Vps45 is involved in iron uptake, mitochondrial function and virulence in the pathogenic fungus Cryptococcus neoformans

Shear stress augments mitochondrial ATP generation that triggers ATP release and Ca²⁺signaling in vascular endothelial cells

Salsolinol Attenuates Doxorubicin-Induced Chronic Heart Failure in Rats and Improves Mitochondrial Function in H9c2 Cardiomyocytes

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Mitochondrial Ca 2+ transport in the endothelium: regulation by ions, redox signalling and mechanical forces

Cited by 29 publications

References 206 publications

The Sec1/Munc18 (SM) protein Vps45 is involved in iron uptake, mitochondrial function and virulence in the pathogenic fungus Cryptococcus neoformans

The Sec1/Munc18 (SM) protein Vps45 is involved in iron uptake, mitochondrial function and virulence in the pathogenic fungus Cryptococcus neoformans

Shear stress augments mitochondrial ATP generation that triggers ATP release and Ca2+signaling in vascular endothelial cells

Salsolinol Attenuates Doxorubicin-Induced Chronic Heart Failure in Rats and Improves Mitochondrial Function in H9c2 Cardiomyocytes

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Product

Resources

About

Mitochondrial Ca ²⁺ transport in the endothelium: regulation by ions, redox signalling and mechanical forces

Shear stress augments mitochondrial ATP generation that triggers ATP release and Ca²⁺signaling in vascular endothelial cells