Dual role of inorganic polyphosphate in cardiac myocytes: The importance of polyP chain length for energy metabolism and mPTP activation

Lea K. Seidlmayer, Maria R. Gomez-Garcia, Toshikazu Shiba, George A. Porter, Evgeny V. Pavlov, Donald M Bers, Elena N. Dedkova

Research output: Contribution to journalArticle

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Abstract

We have previously demonstrated that inorganic polyphosphate (polyP) is a potent activator of the mitochondrial permeability transition pore (mPTP) in cardiac myocytes. PolyP depletion protected against Ca2+-induced mPTP opening, however it did not prevent and even exacerbated cell death during ischemia-reperfusion (I/R). The central goal of this study was to investigate potential molecular mechanisms underlying these dichotomous effects of polyP on mitochondrial function. We utilized a Langendorff-perfused heart model of I/R to monitor changes in polyP size and chain length at baseline, 20 min no-flow ischemia, and 15 min reperfusion. Freshly isolated cardiac myocytes and mitochondria from C57BL/6J (WT) and cyclophilin D knock-out (CypD KO) mice were used to measure polyP uptake, mPTP activity, mitochondrial membrane potential, respiration and ATP generation. We found that I/R induced a significant decrease in polyP chain length. We, therefore, tested, the ability of synthetic polyPs with different chain length to accumulate in mitochondria and induce mPTP. Both short and long chain polyPs accumulated in mitochondria in oligomycin-sensitive manner implicating potential involvement of mitochondrial ATP synthase in polyP transport. Notably, only short-chain polyP activated mPTP in WT myocytes, and this effect was prevented by mPTP inhibitor cyclosprorin A and absent in CypD KO myocytes. To the contrary, long-chain polyP suppressed mPTP activation, and enhanced ADP-linked respiration and ATP production. Our data indicate that 1) effect of polyP on cardiac function strongly depends on polymer chain length; and 2) short-chain polyPs (as increased in ischemia-reperfusion) induce mPTP and mitochondrial uncoupling, while long-chain polyPs contribute to energy generation and cell metabolism.

Original languageEnglish (US)
Pages (from-to)177-189
Number of pages13
JournalArchives of Biochemistry and Biophysics
Volume662
DOIs
StatePublished - Feb 15 2019

Fingerprint

Polyphosphates
Chain length
Cardiac Myocytes
Energy Metabolism
Chemical activation
Polyps
Reperfusion
Ischemia
Mitochondria
Muscle Cells
Respiration
Adenosine Triphosphate
Mitochondrial Proton-Translocating ATPases
Oligomycins
mitochondrial permeability transition pore
Mitochondrial Membrane Potential
Cell death
Metabolism
Knockout Mice
Adenosine Diphosphate

Keywords

  • Animal models of human disease
  • ATP synthase
  • Bioenergetics
  • Inorganic polyphosphate
  • Ischemia-reperfusion injury
  • Metabolism
  • Mitochondrial metabolism
  • Mitochondrial permeability transition pore

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

Cite this

Dual role of inorganic polyphosphate in cardiac myocytes : The importance of polyP chain length for energy metabolism and mPTP activation. / Seidlmayer, Lea K.; Gomez-Garcia, Maria R.; Shiba, Toshikazu; Porter, George A.; Pavlov, Evgeny V.; Bers, Donald M; Dedkova, Elena N.

In: Archives of Biochemistry and Biophysics, Vol. 662, 15.02.2019, p. 177-189.

Research output: Contribution to journalArticle

Seidlmayer, Lea K. ; Gomez-Garcia, Maria R. ; Shiba, Toshikazu ; Porter, George A. ; Pavlov, Evgeny V. ; Bers, Donald M ; Dedkova, Elena N. / Dual role of inorganic polyphosphate in cardiac myocytes : The importance of polyP chain length for energy metabolism and mPTP activation. In: Archives of Biochemistry and Biophysics. 2019 ; Vol. 662. pp. 177-189.
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T2 - The importance of polyP chain length for energy metabolism and mPTP activation

AU - Seidlmayer, Lea K.

AU - Gomez-Garcia, Maria R.

AU - Shiba, Toshikazu

AU - Porter, George A.

AU - Pavlov, Evgeny V.

AU - Bers, Donald M

AU - Dedkova, Elena N.

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AB - We have previously demonstrated that inorganic polyphosphate (polyP) is a potent activator of the mitochondrial permeability transition pore (mPTP) in cardiac myocytes. PolyP depletion protected against Ca2+-induced mPTP opening, however it did not prevent and even exacerbated cell death during ischemia-reperfusion (I/R). The central goal of this study was to investigate potential molecular mechanisms underlying these dichotomous effects of polyP on mitochondrial function. We utilized a Langendorff-perfused heart model of I/R to monitor changes in polyP size and chain length at baseline, 20 min no-flow ischemia, and 15 min reperfusion. Freshly isolated cardiac myocytes and mitochondria from C57BL/6J (WT) and cyclophilin D knock-out (CypD KO) mice were used to measure polyP uptake, mPTP activity, mitochondrial membrane potential, respiration and ATP generation. We found that I/R induced a significant decrease in polyP chain length. We, therefore, tested, the ability of synthetic polyPs with different chain length to accumulate in mitochondria and induce mPTP. Both short and long chain polyPs accumulated in mitochondria in oligomycin-sensitive manner implicating potential involvement of mitochondrial ATP synthase in polyP transport. Notably, only short-chain polyP activated mPTP in WT myocytes, and this effect was prevented by mPTP inhibitor cyclosprorin A and absent in CypD KO myocytes. To the contrary, long-chain polyP suppressed mPTP activation, and enhanced ADP-linked respiration and ATP production. Our data indicate that 1) effect of polyP on cardiac function strongly depends on polymer chain length; and 2) short-chain polyPs (as increased in ischemia-reperfusion) induce mPTP and mitochondrial uncoupling, while long-chain polyPs contribute to energy generation and cell metabolism.

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