Regulation of mitochondrial matrix volume

Kaasik, Allen; Safiulina, Dzhamilja; Zharkovsky, Alexander; Veksler, Vladimir

doi:10.1152/ajpcell.00272.2006

Cited by 225 publications

(190 citation statements)

References 63 publications

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“…Thus, mitochondrial swelling and deenergization may occur independent of the PTP. 62 In conclusion, our data indicate that mitochondrial deenergization triggered by Bcl-2-sensitive changes in calcium flux promote flavopiridol-induced CLL cell death. These mitochondrial events were contemporaneous with the onset of tumor cell lysis in CLL patients treated with flavopiridol using an effective new schedule.…”

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confidence: 59%

Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium

Hussain

Lucas

Johnson

et al. 2008

Blood

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Effective administration of flavopiridol in advanced-stage chronic lymphocytic leukemia (CLL) is often associated with early biochemical evidence of tumor cell lysis. Previous work using other cell types showed that flavopiridol impacts mitochondria, and in CLL cells flavopiridol down-regulates the mitochondrial protein Mcl-1. We therefore investigated mitochondrial structure and function in flavopiridol-treated CLL patient cells and in the lymphoblastic cell line 697 using concentrations and times at which tumor lysis is observed in treated patients. Mitochondrial membrane depolarization was detected in flavopiridol-treated CLL cells by 6 hours, well before the onset of cell death. Flavopiridol-induced mitochondrial depolarization was not blocked by caspase inhibitors or by the calcium chelator EGTA, but was reduced by Bcl-2 overexpression. Intracellular calcium mobilization was noted at early time points using fluorescence microscopy. Furthermore, electron paramagnetic resonance oximetry showed a gradual but significant reduction in cellular oxygen consumption rate by 6 hours, corresponding with ultrastructural mitochondrial damage detected by electron microscopy. IntroductionFlavopiridol is a semisynthetic flavone (N-methylpiperidinyl chlorophenyl flavone) that is considered to act broadly as a cyclindependent kinase (CDK) inhibitor. 1 However, the in vivo mechanism of action of flavopiridol is not well understood, and may involve actions other than or inclusive of CDK inhibition. Our group recently demonstrated significant clinical efficacy of flavopiridol in patients with refractory chronic lymphocytic leukemia (CLL) using a novel schedule of administration. 2 Approximately 50% of CLL patients who receive flavopiridol using this schedule exhibit biochemical signs of tumor lysis (elevated potassium and phosphate levels, reduced calcium levels) occurring as early as 4.5 hours after treatment initiation. In limited cases with highly elevated peripheral white blood cell counts, this tumor lysis can be severe enough to require dialysis. This observation suggests that flavopiridol, when effectively administered, induces very rapid cell death that is atypical of classical apoptosis. However, more work is needed to understand this process and to better predict which patients may experience severe tumor lysis.Multiple previous studies in different cell types have incriminated mitochondrial mechanisms in flavopiridol-induced apoptosis, although conditions and time points under which this is noted vary widely and are often reported in combination with other agents. [3][4][5][6][7][8][9][10][11] Several reports showed that flavopiridol induces mitochondrial membrane disruption and release of cytochrome c in the U937 human monoblastic leukemia cell line and that these effects were potentiated by phorbol myristate acetate (PMA). 4,9,10 This process in U937 cells was noted to be partially caspase independent, as a general caspase inhibitor blocked flavopiridol-induced loss of mitochondrial membrane potential (⌬⌿ m ) but ...

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confidence: 59%

Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium

Hussain

Lucas

Johnson

et al. 2008

Blood

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“…ATP is consumed at approximately the same rate as it is synthesized. Our data indicate that high concentrations of [Cl − ] i may impair mitochondrial function, thereby decreasing ATP synthesis, probably because protein crowding is even higher in mitochondria than in the cytosol (63) and because alterations in matrix volume strongly affect mitochondrial function (64,65). Accordingly, hypertonicity initially decreases the volume of isolated mitochondria (64), and even mild hypertonic exposure (an increase of 60 mOsmol/kg) was reported to dissipate ΔΨ in cultured Vero cells within minutes of challenge (30).…”

Section: Discussionmentioning

confidence: 96%

“…We interpret our data as evidence that mitochondria are able to adapt and restore ATP production despite elevated intracellular ionic strength, but that this adaptation takes a few minutes. This adaptation may involve restored K + equilibrium across the mitochondrial inner membrane, because matrix volume is controlled by the kinetic equilibrium between K + entry and efflux (64,65). Other mitochondrial ion transporters also may be involved in restoring mitochondrial ΔΨ.…”

Section: Discussionmentioning

confidence: 99%

Ionic imbalance, in addition to molecular crowding, abates cytoskeletal dynamics and vesicle motility during hypertonic stress

Nunes

Roth

Meda

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Cell volume homeostasis is vital for the maintenance of optimal protein density and cellular function. Numerous mammalian cell types are routinely exposed to acute hypertonic challenge and shrink. Molecular crowding modifies biochemical reaction rates and decreases macromolecule diffusion. Cell volume is restored rapidly by ion influx but at the expense of elevated intracellular sodium and chloride levels that persist long after challenge. Although recent studies have highlighted the role of molecular crowding on the effects of hypertonicity, the effects of ionic imbalance on cellular trafficking dynamics in living cells are largely unexplored. By tracking distinct fluorescently labeled endosome/vesicle populations by live-cell imaging, we show that vesicle motility is reduced dramatically in a variety of cell types at the onset of hypertonic challenge. Live-cell imaging of actin and tubulin revealed similar arrested microfilament motility upon challenge. Vesicle motility recovered long after cell volume, a process that required functional regulatory volume increase and was accelerated by a return of extracellular osmolality to isosmotic levels. This delay suggests that, although volume-induced molecular crowding contributes to trafficking defects, it alone cannot explain the observed effects. Using fluorescent indicators and FRET-based probes, we found that intracellular ATP abundance and mitochondrial potential were reduced by hypertonicity and recovered after longer periods of time. Similar to the effects of osmotic challenge, isovolumetric elevation of intracellular chloride concentration by ionophores transiently decreased ATP production by mitochondria and abated microfilament and vesicle motility. These data illustrate how perturbed ionic balance, in addition to molecular crowding, affects membrane trafficking.electrolyte | cell volume | hypertonicity | membrane trafficking | mitochondria

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“…Mitochondrial matrix volume is controlled primarily by potassium fluxes and many studies have implicated potassium channels in regulating apoptosis. 33,34 Furthermore, BCL2 inhibits mitochondrial potassium uptake in some apoptotic models. 35 Thus, the ABT-737-induced MIMP observed in the present study may be related to a loss of BCL2 regulation of potassium fluxes.…”

Section: Discussionmentioning

confidence: 99%

A novel paradigm for rapid ABT-737-induced apoptosis involving outer mitochondrial membrane rupture in primary leukemia and lymphoma cells

et al. 2008

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Primary chronic lymphocytic leukemia (CLL) cells are exquisitely sensitive to ABT-737, a small molecule BCL2-antagonist, which induces many of the classical biochemical and ultrastructural features of apoptosis, including BAX/BAK oligomerization, cytochrome c release, caspase activation and chromatin condensation. Surprisingly, ABT-737 also induces mitochondrial inner membrane permeabilization (MIMP) resulting in mitochondrial matrix swelling and rupture of the outer mitochondrial membrane (OMM), so permitting the rapid efflux of cytochrome c from mitochondrial cristae and facilitating rapid caspase activation and apoptosis. BAX and BAK appear to be involved in the OMM discontinuities as they localize to the OMM break points. Notably, ABT-737 induced mitochondrial matrix swelling and OMM discontinuities in other primary B-cell malignancies, including mantle cell, follicular and marginal zone lymphoma cells but not in several cell lines studied. Thus, we describe a new paradigm of apoptosis in primary B-cell malignancies, whereby targeting of BCL2 results in all the classical features of apoptosis together with OMM rupture independent of caspase activation. This mechanism may be far more prevalent than hitherto recognized due to the failure of most methods, used to measure apoptosis, to recognize such a mechanism.

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Regulation of mitochondrial matrix volume

Cited by 225 publications

References 63 publications

Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium

Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium

Ionic imbalance, in addition to molecular crowding, abates cytoskeletal dynamics and vesicle motility during hypertonic stress

A novel paradigm for rapid ABT-737-induced apoptosis involving outer mitochondrial membrane rupture in primary leukemia and lymphoma cells

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