The Mitochondrial Membrane Permeability Transition Induced by Inorganic Phosphate or Inorganic Arsenate. A Comparative Study

Bravo, Concepciòn; Chávez, Edmundo; Rodríguez, José; Moreno‐Sánchez, Rafael

doi:10.1016/s0305-0491(96)00257-x

Cited by 17 publications

(6 citation statements)

References 39 publications

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“…However, Bernardi’s group reported that the ability of CypD inhibition (genetic or pharmacological) to negatively regulate the MPT pore is surprisingly lost when P i is omitted from the buffer and replaced with other inorganic anions (in order to maintain Ca 2+ uptake into the mitochondria) [20]. This was consistent with earlier studies suggesting that P i could strengthen the inhibitory effect of CsA on MPT in isolated mitochondria [22], and that As i -dependent MPT was less sensitive to CsA [23]. …”

Section: Discussionsupporting

confidence: 82%

Phosphate is not an absolute requirement for the inhibitory effects of cyclosporin A or cyclophilin D deletion on mitochondrial permeability transition

McGee

Baines

2012

Biochemical Journal

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CypD (cyclophilin D) has been established as a critical regulator of the MPT (mitochondrial permeability transition) pore, and pharmacological or genetic inhibition of CypD attenuates MPT in numerous systems. However, it has recently been suggested that the inhibitory effects of CypD inhibition only manifest when Pi (inorganic phosphate) is present, and that inhibition is lost when Pi is replaced by Asi (inorganic arsenate) or Vi (inorganic vanadate). To test this, liver mitochondria were isolated from wild-type and CypD-deficient (Ppif−/−) mice and then incubated in buffer containing Pi, Asi or Vi. MPT was induced under both energized and de-energized conditions by the addition of Ca2+, and the resultant mitochondrial swelling was measured spectrophotometrically. For pharmacological inhibition of CypD, wild-type mitochondria were pre-incubated with CsA (cyclosporin A) before the addition of Ca2+. In energized and de-energized mitochondria, Ca2+ induced MPT regardless of the anion present, although the magnitude differed between Pi, Asi and Vi. However, in all cases, pre-treatment with CsA significantly inhibited MPT. Moreover, these effects were independent of mouse strain, organ type and rodent species. Similarly, attenuation of Ca2+ -induced MPT in the Ppif−/− mitochondria was still observed irrespective of whether Pi, Asi or Vi was present. We conclude that the pharmacological and genetic inhibition of CypD is still able to attenuate MPT even in the absence of Pi.

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Section: Discussionsupporting

confidence: 82%

Phosphate is not an absolute requirement for the inhibitory effects of cyclosporin A or cyclophilin D deletion on mitochondrial permeability transition

McGee

Baines

2012

Biochemical Journal

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“…In cells of myelogenic and lymphatic origin, arsenic trioxide (5-20 µM) or arsenite (20-30 µM) triggered a loss in mitochondrial membrane potential (Larochette et al, 1999;Belzacq et al, 2001;Korper et al, 2004;Rojewski et al, 2004). Arsenate (≥ 1 mM) was also able to induce collapse of the mitochondrial membrane potential in isolated rat kidney mitochondria (Bravo et al, 1997). Low-level arsenic trioxide decreased mitochondrial membrane potential in several renal carcinoma cells lines (2.5-10 µM; Hyun Park et al, 2003) and in normal rat kidney tubular cells, NRK52E (1-2.5 µM; Jimi et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Morphological and functional alterations in human proximal tubular cell line induced by low level inorganic arsenic: evidence for targeting of mitochondria and initiated apoptosis

et al. 2006

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The kidney is a known target organ for arsenic and is critical for both arsenic biotransformation and elimination. Previous studies have demonstrated that at high doses (ppm) inorganic arsenic is toxic to mitochondria primarily by affecting cellular respiration. However, the effect of inorganic arsenic on mitochondria after low level exposures is not known, particularly in the kidney. Thus the functional and morphological effects of low level inorganic arsenic were investigated in a human proximal tubular cell line, HK-2. Mitochondrial function was assessed at subcytotoxic concentrations of arsenite (< or = 10 microm) by examining the alteration of the mitochondrial membrane potential using MitoTracker Red, a mitochondrion selective dye. In a subset of cells, subcytotoxic arsenite led to mitochondrial membrane depolarization, which could subsequently lead to permeability transition and apoptosis. Subcytotoxic arsenite also induced translocation of phosphatidylserine, indicative of early-stage apoptosis. To confirm whether subcytotoxic arsenite induces cellular and/or mitochondrial morphological alterations consistent with initiated apoptosis, HK-2 cells were evaluated with transmission electron microscopy. Classic morphology of apoptosis was not observed with subcytotoxic arsenite exposures; however, evidence of necrotic changes in the cytoplasmic structure and mitochondrial morphology were apparent. Therefore, based on depolarization of mitochondria and the externalization of phosphatidylserine, HK-2 cells appear to initiate apoptosis following subcytotoxic arsenite insult, but morphological changes indicate that HK-2 cells fail to complete apoptosis and ultimately undergo necrosis. Therefore, subcytotoxic arsenite can be sufficiently toxic to mitochondria that they lose their ability to keep the cell on course for apoptotic cell death.

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“…Since the Pi level in hypertrophic chondrocytes is high (for a discussion of chondrocyte Pi and calcium ion concentrations, see Wuthier, 1993), there would be development of a mitochondrial membrane transition state and defective oxidative phosphorylation (Bravo et al, 1997). This type of generalized dysfunction would enhance generation of reactive oxygen species and promote release of cytochrome c. There would also be significant alterations in the redox status of the cell .…”

Section: Discussionmentioning

confidence: 99%

Extracellular phosphate ions cause apoptosis of terminally differentiated epiphyseal chondrocytes

Mansfield

Rajpurohit

Shapiro

1999

Journal Cellular Physiology

108

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Epiphyseal chondrocytes end their life cycle through apoptosis. While this event provides a mechanism for the removal of terminally differentiated cells from cartilage, agents that promote this physiological process have not been defined. To address this issue, using a cell culture technique that models events that take place in the growth plate, we asked the following questions: Can agents that promote chondrocyte maturation and cartilage mineralization serve as specific triggers for cell death? Are chondrocytes susceptible to apoptogens at a singular developmental stage? Treatment of embryonic tibial chondrocytes with inorganic phosphate (Pi) induced death in a dose- and time-dependent manner. Within 48 hr, 3 mM Pi increased chondrocyte death by 30%; lower concentrations of Pi induced death after 48 hr. To ascertain if death was due to apoptosis, we evaluated Pi-induced death by a number of different methods and compared the results to those induced by the apoptogen, staurosporine. Analysis of the death process indicated that cartilage cells shared many of the common biological features of the apoptotic process. Thus, there was DNA fragmentation, terminal deoxynucleotidyl transferase (TUNEL) labeling, an increase in cells in the sub-G1 fraction of the cell cycle, and morphological evidence of apoptosis. To explore the specificity of the Pi effect, the experiment was repeated using embryonic sternal cephalic and caudal chondrocytes, cells that are at an earlier developmental stage than the terminally differentiated tibial cells. We noted that these cells remained vital despite a major increase in the medium Pi content. Results of this study suggest that Pi is a stage-specific inducer of apoptosis in maturing chondrocytes and that this role may be linked to chondrocyte maturation and mineralization of the extracellular matrix.

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The Mitochondrial Membrane Permeability Transition Induced by Inorganic Phosphate or Inorganic Arsenate. A Comparative Study

Cited by 17 publications

References 39 publications

Phosphate is not an absolute requirement for the inhibitory effects of cyclosporin A or cyclophilin D deletion on mitochondrial permeability transition

Phosphate is not an absolute requirement for the inhibitory effects of cyclosporin A or cyclophilin D deletion on mitochondrial permeability transition

Morphological and functional alterations in human proximal tubular cell line induced by low level inorganic arsenic: evidence for targeting of mitochondria and initiated apoptosis

Extracellular phosphate ions cause apoptosis of terminally differentiated epiphyseal chondrocytes

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