Mitochondrial Permeability Transition and Swelling Can Occur Reversibly without Inducing Cell Death in Intact Human Cells

Minamikawa, Tetsuhiro; Williams, David A.; Bowser, David N.; Nagley, Phillip

doi:10.1006/excr.1998.4290

Cited by 169 publications

(108 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1B). This pattern of regions of hyperpolarized and depolarized mitochondria has been reported in other cell types and is considered to reflect uneven distribution of proton circuits, respiration, ATP synthesis, and localized Ca 2ϩ inside mitochondria (21). DHR-123 is colorless, but becomes fluorescent upon oxidation, for example in the presence of H 2 O 2 .…”

Section: Neutrophils Possess a Complex Mitochondrial Networksupporting

confidence: 56%

“…MitoTracker Red (20,21) fluorescence is indicative of mitochondria with active membrane potential, and its fluorescence is diminished in cells that have lost their membrane potential. MitoTracker Red staining revealed an extensive mitochondrial network throughout the cytosol, surrounding the nuclear lobes that are seen as unstained regions in unfixed neutrophils (Fig.…”

Section: Neutrophils Possess a Complex Mitochondrial Networkmentioning

confidence: 99%

“…1A). JC-1 fluorescence has two emission peaks (21,22), with red fluorescence of j-aggregates indicating hyperpolarized mitochondria (high membrane potential) and green fluorescence (JC-1 monomers) due to low mitochondrial membrane potential. The ratio of red to green fluorescence is thus a measure of the mitochondrial membrane potential.…”

Section: Neutrophils Possess a Complex Mitochondrial Networkmentioning

confidence: 99%

See 2 more Smart Citations

The Mitochondrial Network of Human Neutrophils: Role in Chemotaxis, Phagocytosis, Respiratory Burst Activation, and Commitment to Apoptosis

Fossati

Moulding

Spiller

et al. 2003

The Journal of Immunology

316

251

View full text Add to dashboard Cite

It is commonly assumed that human neutrophils possess few, if any, functional mitochondria and that they do not depend on these organelles for cell function. We have used the fluorescent mitochondrial indicators, JC-1, MitoTracker Red, and dihydrorhodamine 123 to show that live neutrophils possess a complex mitochondrial network that extends through the cytoplasm. The membrane potential of these mitochondria was rapidly (within 2 min) disrupted by the addition of FCCP (IC50 = 20 nM), but not by the Fo-ATPase inhibitor, oligomycin (at up to 7 μg/ml). However, inhibition of mitochondrial function with both agents resulted in cell shape changes. Neither activation of the respiratory burst nor phagocytosis of either latex particles or serum-opsonized Staphylococcus aureus was affected by the addition of FCCP or oligomycin. However, FCCP inhibited chemotaxis at concentrations that paralleled disruption of mitochondrial membrane potential. Furthermore, prolonged (2-h) incubation with oligomycin resulted in an impaired ability to activate a respiratory burst and also inhibited chemotaxis. These observations indicate that intact mitochondrial function is required to sustain some neutrophil functions, but not for the rapid initiation of the respiratory burst or phagocytosis. Loss of mitochondrial membrane potential was a very early marker for commitment of neutrophils into apoptosis and preceded the appearance of phosphatidylserine on the cell surface. However, inhibition of mitochondrial function did not accelerate the rate of neutrophil apoptosis. These data shed important insights into the hitherto unrecognized importance of mitochondria in the function of neutrophils during infection and inflammation.

show abstract

Section: Neutrophils Possess a Complex Mitochondrial Networksupporting

confidence: 56%

Section: Neutrophils Possess a Complex Mitochondrial Networkmentioning

confidence: 99%

Section: Neutrophils Possess a Complex Mitochondrial Networkmentioning

confidence: 99%

See 1 more Smart Citation

The Mitochondrial Network of Human Neutrophils: Role in Chemotaxis, Phagocytosis, Respiratory Burst Activation, and Commitment to Apoptosis

Fossati

Moulding

Spiller

et al. 2003

The Journal of Immunology

316

251

View full text Add to dashboard Cite

show abstract

“…In the latter, decreases in Dw m and thus a reduction in ATP for protein synthesis inhibited or delayed apoptosis until such time that reduced ATP levels were the cause of cellular demise (Salvioli et al 2000). Human osteosarcoma cells were observed to undergo mitochondrial permeability transition and mitochondrial swelling in a reversible manner and with the marked absence of apoptosis (Minamikawa et al 1999). Indeed the reversibility of the MPT may explain the heterogeneic response of HepZ mitochondria to STS treatment.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis and Its Suppression in Hepatocytes Culture

Mukwena

Al‐Rubeai

2004

Cytotechnology

View full text Add to dashboard Cite

In order to achieve the goal of developing extracorporeal liver support devices, it is necessary to optimise bioprocess environment such that viability and function are maximised. Optimising culture medium composition and controlling the constitution of the cellular microenvironment within the bioreactor have for many years been considered vital to achieving these aims. Coupled to this is the need to understand apoptosis, the prime suspect in the demise of animal cultures, including those of hepatocytes. Results presented here show that absent nutrients including glucose and amino acids play a substantial part in the induction of apoptosis. The use of chemical apoptosis inhibitors was utilised to investigate key components of hepatic apoptosis where caspases, predominantly caspase 8, were implicated in staurosporine (STS)-induced HepZ apoptosis. Caspase 9 and 3 activation although recorded was of less significance. Interestingly, these results were not consistent with those of mitochondrial membrane depolarisation where inhibition of caspase activation appeared to drive depolarisation. Inhibition of mitochondrial permeability transition and use of anti-oxidants was unsuccessful in reducing apoptosis, caspase activation and mitochondrial membrane depolarisation. In further studies, the anti-apoptotic gene bcl-2 was over-expressed in HepZ, resulting in a cell line that was more robust and resistant to death induced by glucose and cystine deprivation and treatment with STS. Bcl-2 did not however show significant cytoprotectivity where apoptosis was stimulated by deprivation of glutamine and serum. Overall, results indicated that although apoptosis can be curbed by use of chemical inhibitors and genetic manipulation, their success is dependent on apoptotic stimuli.

show abstract

“…A decrease of ⌬⌿ m can occur in a reversible manner without any cytochrome c release and cell death [47][48][49]. ATP depletion alone does not necessarily lead to depolarization of the mitochondria [34].…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of Bcl-2 on Cell Death Triggered under ATP-Depleting Conditions

Single

Leist

Nicotera

2001

Experimental Cell Research

View full text Add to dashboard Cite

The intracellular ATP concentration decides on the onset of either apoptosis or necrosis in Jurkat cells exposed to death stimuli. Bcl-2 can block apoptotic demise, which occurs preferably under conditions of high cellular ATP levels. Here, we investigated the effects of Bcl-2 on the necrotic type of cell demise that prevails under conditions of energy loss. ATP levels were modulated by using mitochondrial inhibitors, such as rotenone or S-nitrosoglutathione, in medium either lacking glucose or supplemented with glucose to stimulate glycolytic ATP generation. Under conditions of ATP depletion, staurosporine (STS) induced >90% necrosis in vector control-transfected cells, whereas bcl-2-transfected cells were protected. Thus, the antiapoptotic protein Bcl-2 can reduce the overall amount of cell death in ATP-depleted cells regardless whether it occurs by apoptosis or necrosis. Cytochrome c release, normally preceding STS-induced necrosis, was also inhibited by Bcl-2. However, Bcl-2 did not prevent an initial STS-induced drop of the mitochondrial membrane potential (⌬⌿ m ). Therefore, the mechanisms whereby Bcl-2 prevents cell death and favors retention of cytochrome c in the mitochondria require neither the maintenance of mitochondrial ⌬⌿ nor the maintenance of normal ATP levels.

show abstract

Mitochondrial Permeability Transition and Swelling Can Occur Reversibly without Inducing Cell Death in Intact Human Cells

Cited by 169 publications

References 34 publications

The Mitochondrial Network of Human Neutrophils: Role in Chemotaxis, Phagocytosis, Respiratory Burst Activation, and Commitment to Apoptosis

The Mitochondrial Network of Human Neutrophils: Role in Chemotaxis, Phagocytosis, Respiratory Burst Activation, and Commitment to Apoptosis

Apoptosis and Its Suppression in Hepatocytes Culture

Differential Effects of Bcl-2 on Cell Death Triggered under ATP-Depleting Conditions

Contact Info

Product

Resources

About