Essential Role of Mitochondrial Ca2+ Uniporter in the Generation of Mitochondrial pH Gradient and Metabolism-Secretion Coupling in Insulin-releasing Cells

Quan, Xianglan; Nguyen, Tuyet Thi; Choi, Seong Kyung; Xu, Shanhua; Das, Ranjan; Kuy, Seung; Kim, Nari; Han, Jin; Wiederkehr, Andreas; Wollheim, Claes B.; Park, Kyu Sang

doi:10.1074/jbc.m114.632547

Cited by 61 publications

(61 citation statements)

References 48 publications

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“…[Ca 2ϩ ] m -mediated pyruvate dehydrogenase activation and increased substrate affinity for the other dehydrogenases could thus facilitate cycle operation during the refilling phase. Quan et al (427) provided apparent support for this hypothesis when they observed that basal and glucose-stimulated respiration were both reduced in INS-1E cells following MCU knockdown. However, a surprising complication was that expression levels of electron transport complexes were severely reduced in the knock-down.…”

Section: If the Effect Of Elevated [Ca 2ϩmentioning

confidence: 68%

“…A similar time course can be seen in the respiratory response of clonal insulinoma cells and human islets to acutely elevated glucose, with an initial doubling of respiration followed by a further increase over the subsequent 50 min (112,184,491). Much of the enhanced proton current is directed through the ATP synthase, rather than the endogenous proton leak, judged by the extent of oligomycin inhibition (FIGURE 3D) (112,147,184,427). To date, I am not aware of any detailed quantitative analysis of the ATPconsuming reactions in the ␤-cell cytosol.…”

Section: If the Effect Of Elevated [Ca 2ϩmentioning

confidence: 75%

“…233,269,323,326,427,459). Maechler et al (323) reported that methyl-pyruvate (rather than pyruvate) supported matrix Ca 2ϩ accumulation and insulin secretion from ␣-toxin-permeabilized INS-1 cells (323).…”

Section: Permeabilized Cell Preparationsmentioning

confidence: 99%

“…Akhmedov et al (12) reported a slow increase in ⌬pH in INS-1E cells in high glucose. With the caveats discussed above, the study of Quan et al (427) indicated a decreased ⌬pH in their knockdown, in which case the lack of a "second-phase" increase in ⌬G p could be ascribed to a straightforward restriction in the total ⌬p. The extent to which mitochondrial Ca 2ϩ accumulation influences ⌬pH depends on the extent to which the parallel uptake of P i , which may be thought of as a H ϩ -H 2 PO 4 Ϫ symport (376,426), discharges the pH gradient.…”

Section: Does Matrix Ca 2ϩ Increase ⌬P?mentioning

confidence: 99%

“…Tarasov et al (511) found no difference in basal ⌬ m , or in mitochondrial hyperpolarization in their MCU knock-down in the first 5 min of high glucose, a period during which "second-phase" effects on ⌬G p had become apparent. Quan et al (427) reported that MCU knockdown did not affect the ability of glucose to hyperpolarize ⌬p, although interpretation was complicated by the decreased expression of electron transport chain components, and the inappropriate JC-1 as a ⌬ m indicator (see Ref. 288).…”

Section: Does Matrix Ca 2ϩ Increase ⌬P?mentioning

confidence: 99%

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The Pancreatic β-Cell: A Bioenergetic Perspective

Nicholls

2016

Physiological Reviews

123

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The pancreatic ␤-cell secretes insulin in response to elevated plasma glucose. This review applies an external bioenergetic critique to the central processes of glucose-stimulated insulin secretion, including glycolytic and mitochondrial metabolism, the cytosolic adenine nucleotide pool, and its interaction with plasma membrane ion channels. The control mechanisms responsible for the unique responsiveness of the cell to glucose availability are discussed from bioenergetic and metabolic control standpoints. The concept of coupling factor facilitation of secretion is critiqued, and an attempt is made to unravel the bioenergetic basis of the oscillatory mechanisms controlling secretion. The need to consider the physiological constraints operating in the intact cell is emphasized throughout. The aim is to provide a coherent pathway through an extensive, complex, and sometimes bewildering literature, particularly for those unfamiliar with the field.

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Section: If the Effect Of Elevated [Ca 2ϩmentioning

confidence: 68%

Section: If the Effect Of Elevated [Ca 2ϩmentioning

confidence: 75%

Section: Permeabilized Cell Preparationsmentioning

confidence: 99%

Section: Does Matrix Ca 2ϩ Increase ⌬P?mentioning

confidence: 99%

Section: Does Matrix Ca 2ϩ Increase ⌬P?mentioning

confidence: 99%

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The Pancreatic β-Cell: A Bioenergetic Perspective

Nicholls

2016

Physiological Reviews

123

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Melatonin reverses the oxidative stress and mitochondrial dysfunction caused by LETM1 silencing

Aral

Demirkesen

Bircan

et al. 2019

Cell Biology International

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LETM1 is a mitochondrial inner‐membrane protein, which is encoded by a gene present in a locus of 4p, which, in turn, is deleted in the Wolf–Hirschhorn Syndrome, and is assumed to be related to its pathogenesis. The cellular damage caused by the deletion is presumably related to oxidative stress. Melatonin has many beneficial roles in protecting mitochondria by scavenging reactive oxygen species, maintaining membrane potential, and improving functions. The aim of this study was to investigate the effects of melatonin administration to LETM1‐silenced mouse embryonic fibroblast cells as a cellular model for LETM1 deficiency. We transfected mouse embryonic fibroblast cells with a pair of siRNA against LETM1 and monitored the oxidative stress and mitochondrial functions with or without melatonin addition. MnSOD expression and aconitase activity decreased and oxidized protein levels increased in LETM1‐silenced cells. LETM1 suppression did not alter the expression of OXPHOS complexes, but the oxygen consumption rates decreased significantly; however, this change was not related to complex I but instead involved complex IV and complex II. Melatonin supplementation effectively normalized the parameters studied, including the oxygen consumption rate. Our findings identified a novel effect of LETM1 deficiency on cellular respiration via complex II as well as a potential beneficial role of melatonin treatment. On the other hand, these effects may be specific to the cell line used and need to be verified in other cell lines.

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The Mitochondrial Ca2+ Uniporter: Structure, Function, and Pharmacology

Mishra

Jhun

Hurst

et al. 2017

Handbook of Experimental Pharmacology

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Mitochondrial Ca2+ uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca2+ uptake and our current understanding of mitochondrial Ca2+ homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca2+ uniporter complex.

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Essential Role of Mitochondrial Ca2+ Uniporter in the Generation of Mitochondrial pH Gradient and Metabolism-Secretion Coupling in Insulin-releasing Cells

Cited by 61 publications

References 48 publications

The Pancreatic β-Cell: A Bioenergetic Perspective

The Pancreatic β-Cell: A Bioenergetic Perspective

Melatonin reverses the oxidative stress and mitochondrial dysfunction caused by LETM1 silencing

The Mitochondrial Ca2+ Uniporter: Structure, Function, and Pharmacology

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