Calcium-dependent physiologic and pathologic stimulus-metabolic response coupling in hepatocytes

Gaspers, Lawrence D.; Mémin, Elisabeth; Thomas, Andrew P.

doi:10.1016/j.ceca.2012.04.009

Cited by 26 publications

(26 citation statements)

References 84 publications

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“…Although NADH oscillations were observed in ex vivo model systems, such as pancreatic islets (Luciani et al, 2006), isolated cardiomyocytes (Zhou et al, 2011), perfused liver (Gaspers et al, 2012) and isolated acini from exocrine glands (Bruce et al, 2004; Voronina et al, 2002), their average period was much slower than what we observed in vivo (12.1 ± 3.1 sec, Av. ± S.D., N=19 vs. tens of seconds to minutes).…”

Section: Resultscontrasting

confidence: 64%

In Vivo Tissue-wide Synchronization of Mitochondrial Metabolic Oscillations

et al. 2014

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Summary Little is known about the spatio-temporal coordination of mitochondrial metabolism in multicellular organisms in situ. Using intravital microscopy in live animals, we here report that mitochondrial metabolism undergoes rapid and periodic oscillations under basal conditions. Notably, mitochondria in vivo behave as a network of functionally coupled oscillators, which maintain a high level of coordination throughout the tissue via the activity of gap junctions. These findings reveal a unique aspect of the relationship between tissue architecture and self-organization of mitochondrial metabolism in vivo.

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Section: Resultscontrasting

confidence: 64%

In Vivo Tissue-wide Synchronization of Mitochondrial Metabolic Oscillations

et al. 2014

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“…Moreover, mitochondrially targeted ROS biosensors have revealed increases in mitochondrial superoxide and hydrogen peroxide levels in primary hepatocytes only after sustained hormone‐induced elevations in [Ca 2+ ] i (Gaspers et al . ). We have also reported that mitochondrial Ca 2+ levels and mitochondrial ROS formation are elevated in hepatocytes from alcohol‐fed rats compared to control (Wang et al .…”

Section: Discussionmentioning

confidence: 97%

“…We have previously reported that susceptibility to mitochondrial PTP transition in isolated liver mitochondria and hepatocytes is enhanced by alcohol feeding (Pastorino & Hoek, ) and sustained increases in cytosolic Ca 2+ can stimulate mitochondrial ROS production (Gaspers et al . ). Therefore, we hypothesized that pathological conditions that alter hormone‐dependent Ca 2+ signalling in the liver may have a profound impact on the health of individual hepatocytes and the organ as a whole.…”

Section: Introductionmentioning

confidence: 97%

Chronic alcohol feeding potentiates hormone‐induced calcium signalling in hepatocytes

Bartlett

Antony

Agarwal

et al. 2017

The Journal of Physiology

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Chronic alcohol consumption causes a spectrum of liver diseases, but the pathogenic mechanisms driving the onset and progression of disease are not clearly defined. We show that chronic alcohol feeding sensitizes rat hepatocytes to Ca -mobilizing hormones resulting in a leftward shift in the concentration-response relationship and the transition from oscillatory to more sustained and prolonged Ca increases. Our data demonstrate that alcohol-dependent adaptation in the Ca signalling pathway occurs at the level of hormone-induced inositol 1,4,5 trisphosphate (IP ) production and does not involve changes in the sensitivity of the IP receptor or size of internal Ca stores. We suggest that prolonged and aberrant hormone-evoked Ca increases may stimulate the production of mitochondrial reactive oxygen species and contribute to alcohol-induced hepatocyte injury. ABSTRACT: 'Adaptive' responses of the liver to chronic alcohol consumption may underlie the development of cell and tissue injury. Alcohol administration can perturb multiple signalling pathways including phosphoinositide-dependent cytosolic calcium ([Ca ] ) increases, which can adversely affect mitochondrial Ca levels, reactive oxygen species production and energy metabolism. Our data indicate that chronic alcohol feeding induces a leftward shift in the dose-response for Ca -mobilizing hormones resulting in more sustained and prolonged [Ca ] increases in both cultured hepatocytes and hepatocytes within the intact perfused liver. Ca increases were initiated at lower hormone concentrations, and intercellular calcium wave propagation rates were faster in alcoholics compared to controls. Acute alcohol treatment (25 mm) completely inhibited hormone-induced calcium increases in control livers, but not after chronic alcohol-feeding, suggesting desensitization to the inhibitory actions of ethanol. Hormone-induced inositol 1,4,5 trisphosphate (IP ) accumulation and phospholipase C (PLC) activity were significantly potentiated in hepatocytes from alcohol-fed rats compared to controls. Removal of extracellular calcium, or chelation of intracellular calcium did not normalize the differences in hormone-stimulated PLC activity, indicating calcium-dependent PLCs are not upregulated by alcohol. We propose that the liver 'adapts' to chronic alcohol exposure by increasing hormone-dependent IP formation, leading to aberrant calcium increases, which may contribute to hepatocyte injury.

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“…The upregulation of Krebs cycle and other Ca 2+ -dependent mitochondrial reactions underpins the regulation of mitochondrial ATP production required for efficient stimulus-metabolism coupling (e.g. [77, 157, 166], reviewed in [55, 156]).…”

Section: Er-mitochondria Junctions As Signalling Nanodomainsmentioning

confidence: 99%

Mitochondrial junctions with cellular organelles: Ca2+ signalling perspective

Tepikin

2018

Pflugers Arch - Eur J Physiol

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Cellular organelles form multiple junctional complexes with one another and the emerging research area dealing with such structures and their functions is undergoing explosive growth. A new research journal named “Contact” has been recently established to facilitate the development of this research field. The current consensus is to define an organellar junction by the maximal distance between the participating organelles; and the gap of 30 nm or less is considered appropriate for classifying such structures as junctions or membrane contact sites. Ideally, the organellar junction should have a functional significance, i.e. facilitate transfer of calcium, sterols, phospholipids, iron and possibly other substances between the organelles (Carrasco and Meyer in Annu Rev Biochem 80:973–1000, 2011; Csordas et al. in Trends Cell Biol 28:523–540, 2018; Phillips and Voeltz in Nat Rev Mol Cell Biol 17:69–82, 2016; Prinz in J Cell Biol 205:759–769, 2014). It is also important to note that the junction is not just a result of a random organelle collision but have active and specific formation, stabilisation and disassembly mechanisms. The nature of these mechanisms and their role in physiology/pathophysiology are the main focus of an emerging research field. In this review, we will briefly describe junctional complexes formed by cellular organelles and then focus on the junctional complexes that are formed by mitochondria with other organelles and the role of these complexes in regulating Ca2+ signalling.

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Calcium-dependent physiologic and pathologic stimulus-metabolic response coupling in hepatocytes

Cited by 26 publications

References 84 publications

In Vivo Tissue-wide Synchronization of Mitochondrial Metabolic Oscillations

In Vivo Tissue-wide Synchronization of Mitochondrial Metabolic Oscillations

Chronic alcohol feeding potentiates hormone‐induced calcium signalling in hepatocytes

Mitochondrial junctions with cellular organelles: Ca2+ signalling perspective

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