Role of Ca<sup>2+</sup> in regulating the level of mitochondrial pyrophosphate

Otto, David A.; Cook, George A.

doi:10.1016/0014-5793(82)81328-8

Cited by 20 publications

(14 citation statements)

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“…The order of magnitude difference between the sensitivity of the isolated pyrophosphatase and the matrix PPi content to [Ca2"] resembles that between the K05 for the activation of purified pyruvate dehydrogenase phosphate phosphatase by Ca2" and for the activation by extramitochondrial Ca2" of pyruvate dehydrogenase within intact mitochondria (Denton & McCormack, 1985;Denton et al, 1987) provided, such as in the presence of butyrate, whose intra-mitochondrial activation produces PPi, the effects of inhibiting the pyrophosphatase with Ca2~are even more pronounced and matrix PP. can increase 30-fold or more in the presence of sub-micromolar Ca2" (Davidson & Halestrap, 1987Otto & Cook, 1982). The source of PPi in the absence of butyrate is unknown, but may be a proton-translocating pyrophosphatase (Volk et al, 1982;Baltscheffsky & Nyren, 1984 sensitive to physiological changes in [Ca2"].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of mitochondrial-matrix inorganic pyrophosphatase by physiological [Ca2+], and its role in the hormonal regulation of mitochondrial matrix volume

Davidson

Halestrap

1989

Biochemical Journal

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1. The pyrophosphatase activity in cytosolic and mitochondrial fractions of rat liver was 1.7 and 0.26 units/mg of protein respectively when assayed at 37 degrees C in the presence of physiological [Mg2+] (0.3 mM). 2. Approx. 80% of the mitochondrial pyrophosphatase was inaccessible to extramitochondrial PPi, of which 40% represented soluble matrix enzyme (0.38 unit/mg of matrix protein). 3. Ca2+ inhibited the soluble matrix enzyme; the effective K0.5 for inhibition increased as [Mg2+], an essential cofactor of the enzyme, increased. Measured values were 0.39, 1.15, 3.7, 8.3 and 12.5 microM at 0.04 mM-, 0.1 mM-, 0.3 mM-, 0.6 mM- and 1 mM-Mg2+ respectively. 4. The data were analysed by a kinetic model similar to that for yeast pyrophosphatase, which assumes the substrate to be MgPPi (Km 5 microM) with Mg2+ also activating at an additional site (K0.5 23 microM). Ca2+ inhibits through the formation of CaPPi, a strong competitive inhibitor (Ki 0.067 microM). 5. Heart mitochondria also contain a soluble matrix pyrophosphatase of similar activity to that of liver mitochondria and with the same sensitivity to [Ca2+]. 6. The data provide an explanation for the increase in mitochondrial PPi, mediated by Ca2+, which is responsible for the increase in matrix volume induced by gluconeogenic hormones [Davidson & Halestrap (1988) Biochem. J. 254, 379-384].

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Section: Discussionmentioning

confidence: 99%

Inhibition of mitochondrial-matrix inorganic pyrophosphatase by physiological [Ca2+], and its role in the hormonal regulation of mitochondrial matrix volume

Davidson

Halestrap

1989

Biochemical Journal

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“…As summarized in Table 1, the swelling induced by 0.6 mM-butyrate was accompanied by a 2-fold increase in mitochondrial PPi content in either the presence or the absence of ATP. This may be explained by activation of butyrate to butyryl-CoA within the mitochondrial matrix (Aas & Bremer, 1968;Otto & Cook, 1982), which were incubated at 37°C (in an orbital water bath) in a sealed 70 ml plastic container containing 2.5 ml of KCI medium and 1 mM-MgATP. After 2 min preincubation, either 0.5 mM-CaCl2 (corresponding to an initial [Ca24] of 8 /zM) or 0.6 mM-butyrate was added and incubation continued for the required time before removal of samples for PP1 determination (i) as described in Fig.…”

Section: Role Of Ca2l and Pp1 In Mitochondrial Swellingmentioning

confidence: 99%

“…This suggested that there might be some involvement of the adenine nucleotide transporter in the swelling process. Otto & Cook (1982) have reported that incubating liver mitochondria with high [Ca2l] in the presence of butyrate led to large accumulation of PP1 within the matrix. In studies on the production of inositol phosphate metabolites by a crude mitochondrial fraction, using high-voltage electrophoresis at pH 1.8, we sometimes detected an increase in PPi in response to submicromolar [Ca2l] (Whipps et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

Liver mitochondrial pyrophosphate concentration is increased by Ca2+ and regulates the intramitochondrial volume and adenine nucleotide content

Davidson

Halestrap

1987

Biochemical Journal

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1. The matrix pyrophosphate (PPi) content of isolated energized rat liver mitochondria incubated in the presence of ATP, Mg2+, Pi and respiratory substrate was about 100 pmol/mg of protein. 2. After incubation with sub-micromolar [Ca2+], this was increased by as much as 300%. There was a correlation between the effects of Ca2+ on PPi and on the increase in matrix volume reported previously [Halestrap, Quinlan, Whipps & Armston (1986) Biochem. J. 236, 779-787]. Half-maximal effects were seen at 0.3 microM-Ca2+. 3. Coincident with these effects, the total adenine nucleotide content increased in a carboxyatractyloside-sensitive manner. 4. Incubation with 0.2-0.5 mM-butyrate induced similar but smaller effects on mitochondrial swelling and matrix PPi and total adenine nucleotide content. Addition of butyrate after Ca2+, or vice versa, caused Ca2+-induced mitochondrial swelling to stop or reverse, while matrix PPi increased 30-fold. 5. Addition of atractyloside or the omission of ATP from incubations greatly enhanced swelling induced by Ca2+ without increasing matrix PPi. 6. Swelling of mitochondria incubated under de-energized conditions in iso-osmotic KSCN was progressively enhanced by the addition of increasing concentrations of PPi (1-20 mM) or valinomycin. 7. In iso-osmotic potassium pyrophosphate swelling was slow initially, but accelerated with time. This acceleration was inhibited by ADP, whereas carboxyatractyloside induced rapid swelling. Swelling in other iso-osmotic PPi salts showed that the rate of entry decreased in the order NH4+ greater than K+ greater than Na+ greater than Li+, whereas choline, tetramethylammonium and Tris did not enter. It is suggested that the adenine nucleotide translocase transports small univalent cations when PPi is bound and that PPi can also be transported when the transporter is in the conformation induced by carboxyatractyloside. 8. It is concluded that Ca2+ and butyrate cause swelling of energized mitochondria through this effect of PPi on K+ permeability of the mitochondrial inner membrane. 9. Freeze-clamped livers from rats treated with glucagon or phenylephrine show 30-50% increases in tissue PPi. It is proposed that Ca2+-mediated increases in mitochondrial PPi are responsible for the increase in matrix volume and total adenine nucleotide content observed after hormone treatment.

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“…Studies in both this and other laboratories have shown that when liver mitochondria are exposed to both butyrate and ea 2 + together, there is a massive 339 increase in PP i to values twentyfold above basal or more (Otto & Cook, 1982;Davidson & Halestrap, 1987). This is far greater than the sum of the effects of either agent on its own and may imply that Ca 2 + is inhibiting the breakdown of the PP i that is produced by the activation of butyrate to butyryl-CoA There appears to be significant pyrophosphatase activity associated with the mitochondrial matrix and this has been shown to be inhibited by Ca 2 +, but only at concentrations far in excess of those found physiologically (Irie et aI., 1970;Yolk et aI., 1982Yolk et aI., , 1983.…”

Section: The Synthesis and Breakdown Of Pp I In The Mitochondriamentioning

confidence: 55%

Anion Carriers of Mitochondrial Membranes

Azzi¹,

Nałęz²,

Nałȩcz³

et al. 1989

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Role of Ca²⁺ in regulating the level of mitochondrial pyrophosphate

Cited by 20 publications

References 28 publications

Inhibition of mitochondrial-matrix inorganic pyrophosphatase by physiological [Ca2+], and its role in the hormonal regulation of mitochondrial matrix volume

Inhibition of mitochondrial-matrix inorganic pyrophosphatase by physiological [Ca2+], and its role in the hormonal regulation of mitochondrial matrix volume

Liver mitochondrial pyrophosphate concentration is increased by Ca2+ and regulates the intramitochondrial volume and adenine nucleotide content

Anion Carriers of Mitochondrial Membranes

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Role of Ca2+ in regulating the level of mitochondrial pyrophosphate

Cited by 20 publications

References 28 publications

Inhibition of mitochondrial-matrix inorganic pyrophosphatase by physiological [Ca2+], and its role in the hormonal regulation of mitochondrial matrix volume

Inhibition of mitochondrial-matrix inorganic pyrophosphatase by physiological [Ca2+], and its role in the hormonal regulation of mitochondrial matrix volume

Liver mitochondrial pyrophosphate concentration is increased by Ca2+ and regulates the intramitochondrial volume and adenine nucleotide content

Anion Carriers of Mitochondrial Membranes

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Role of Ca²⁺ in regulating the level of mitochondrial pyrophosphate