A cardiac mitochondrial fgfr1 mediates the antithetical effects of fgf2 isoforms on permeability transition

Wattamon Srisakuldee; Barbara E. Nickel; Robert R. Fandrich; Feixong Zhang; Kishore B.S. Pasumarthi; Elissavet Kardami

doi:10.3390/cells10102735

A cardiac mitochondrial fgfr1 mediates the antithetical effects of fgf2 isoforms on permeability transition

Wattamon Srisakuldee, Barbara E. Nickel, Robert R. Fandrich, Feixong Zhang, Kishore B.S. Pasumarthi, Elissavet Kardami

Medicine

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

Abstract

Mitochondria, abundant organelles in high energy demand cells such as cardiomyocytes, can determine cell death or survival by regulating the opening of mitochondrial permeability transition pore, mPTP. We addressed the hypothesis that the growth factor FGF2, known to reside in intracellular locations, can directly influence mitochondrial susceptibility to mPTP opening. Rat cardiac subsarcolemmal (SSM) or interfibrillar (IFM) mitochondrial suspensions exposed directly to rat 18 kDa low molecular weight (Lo-) FGF2 isoform displayed increased resistance to calcium overload-induced mPTP, measured spectrophotometrically as “swelling”, or as cytochrome c release from mitochondria. Inhibition of mitochondrial protein kinase C epsilon abrogated direct Lo-FGF2 mito-protection. Exposure to the rat 23 kDa high molecular weight (Hi) FGF2 isoform promoted cytochrome c release from SSM and IFM under nonstressed conditions. The effect of Hi-FGF2 was prevented by mPTP inhibitors, pre-exposure to Lo-FGF2, and okadaic acid, a serine/threonine phosphatase inhibitor. Western blotting and immunoelectron microscopy pointed to the presence of immunoreactive FGFR1 in cardiac mitochondria in situ. The direct mito-protective effect of Lo-FGF2, as well as the deleterious effect of Hi-FGF2, were prevented by FGFR1 inhibitors and FGFR1 neu-tralizing antibodies. We propose that intracellular FGF2 isoforms can modulate mPTP opening by interacting with mito-FGFR1 and relaying isoform-specific intramitochondrial signal transduction.

Original language	English
Article number	2735
Journal	Cells
Volume	10
Issue number	10
DOIs	https://doi.org/10.3390/cells10102735
Publication status	Published - Oct 2021

Bibliographical note

Funding Information:
Funding: This research was funded (E.K.) by the Canadian Institutes for Health Research (CIHR) and the Heart and Stroke Foundation of Canada (HSFC).

Funding Information:
In contrast to Lo-FGF2, exposure to Hi-FGF2 was considered detrimental as it promoted cytochrome c release through mPTP opening. The involvement of mPTP was supported by the ability of two different mPTP inhibitors, SFA, and CsA to block the Hi-FGF2 induced cytochrome c release to the supernatant fraction of mitochondrial suspensions. Indirect support for mPTP involvement was provided by the ability of Lo-FGF2 (which prevents calcium overload-induced mPTP) to also prevent the effect of Hi-FGF2. The release of cytochrome c from mitochondria is an indicator of mitochondrial dysfunction and deterioration; furthermore, in the cellular context, cytochrome c release to the cytosol stimulates a series of events that promote cell death [34].

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

ASJC Scopus Subject Areas

General Medicine

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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Cite this

@article{ab96253503644b4b8f40e25c17310779,

title = "A cardiac mitochondrial fgfr1 mediates the antithetical effects of fgf2 isoforms on permeability transition",

abstract = "Mitochondria, abundant organelles in high energy demand cells such as cardiomyocytes, can determine cell death or survival by regulating the opening of mitochondrial permeability transition pore, mPTP. We addressed the hypothesis that the growth factor FGF2, known to reside in intracellular locations, can directly influence mitochondrial susceptibility to mPTP opening. Rat cardiac subsarcolemmal (SSM) or interfibrillar (IFM) mitochondrial suspensions exposed directly to rat 18 kDa low molecular weight (Lo-) FGF2 isoform displayed increased resistance to calcium overload-induced mPTP, measured spectrophotometrically as “swelling”, or as cytochrome c release from mitochondria. Inhibition of mitochondrial protein kinase C epsilon abrogated direct Lo-FGF2 mito-protection. Exposure to the rat 23 kDa high molecular weight (Hi) FGF2 isoform promoted cytochrome c release from SSM and IFM under nonstressed conditions. The effect of Hi-FGF2 was prevented by mPTP inhibitors, pre-exposure to Lo-FGF2, and okadaic acid, a serine/threonine phosphatase inhibitor. Western blotting and immunoelectron microscopy pointed to the presence of immunoreactive FGFR1 in cardiac mitochondria in situ. The direct mito-protective effect of Lo-FGF2, as well as the deleterious effect of Hi-FGF2, were prevented by FGFR1 inhibitors and FGFR1 neu-tralizing antibodies. We propose that intracellular FGF2 isoforms can modulate mPTP opening by interacting with mito-FGFR1 and relaying isoform-specific intramitochondrial signal transduction.",

author = "Wattamon Srisakuldee and Nickel, {Barbara E.} and Fandrich, {Robert R.} and Feixong Zhang and Pasumarthi, {Kishore B.S.} and Elissavet Kardami",

note = "Funding Information: Funding: This research was funded (E.K.) by the Canadian Institutes for Health Research (CIHR) and the Heart and Stroke Foundation of Canada (HSFC). Funding Information: In contrast to Lo-FGF2, exposure to Hi-FGF2 was considered detrimental as it promoted cytochrome c release through mPTP opening. The involvement of mPTP was supported by the ability of two different mPTP inhibitors, SFA, and CsA to block the Hi-FGF2 induced cytochrome c release to the supernatant fraction of mitochondrial suspensions. Indirect support for mPTP involvement was provided by the ability of Lo-FGF2 (which prevents calcium overload-induced mPTP) to also prevent the effect of Hi-FGF2. The release of cytochrome c from mitochondria is an indicator of mitochondrial dysfunction and deterioration; furthermore, in the cellular context, cytochrome c release to the cytosol stimulates a series of events that promote cell death [34]. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = oct,

doi = "10.3390/cells10102735",

language = "English",

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T1 - A cardiac mitochondrial fgfr1 mediates the antithetical effects of fgf2 isoforms on permeability transition

AU - Srisakuldee, Wattamon

AU - Nickel, Barbara E.

AU - Fandrich, Robert R.

AU - Zhang, Feixong

AU - Pasumarthi, Kishore B.S.

AU - Kardami, Elissavet

N1 - Funding Information: Funding: This research was funded (E.K.) by the Canadian Institutes for Health Research (CIHR) and the Heart and Stroke Foundation of Canada (HSFC). Funding Information: In contrast to Lo-FGF2, exposure to Hi-FGF2 was considered detrimental as it promoted cytochrome c release through mPTP opening. The involvement of mPTP was supported by the ability of two different mPTP inhibitors, SFA, and CsA to block the Hi-FGF2 induced cytochrome c release to the supernatant fraction of mitochondrial suspensions. Indirect support for mPTP involvement was provided by the ability of Lo-FGF2 (which prevents calcium overload-induced mPTP) to also prevent the effect of Hi-FGF2. The release of cytochrome c from mitochondria is an indicator of mitochondrial dysfunction and deterioration; furthermore, in the cellular context, cytochrome c release to the cytosol stimulates a series of events that promote cell death [34]. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/10

Y1 - 2021/10

N2 - Mitochondria, abundant organelles in high energy demand cells such as cardiomyocytes, can determine cell death or survival by regulating the opening of mitochondrial permeability transition pore, mPTP. We addressed the hypothesis that the growth factor FGF2, known to reside in intracellular locations, can directly influence mitochondrial susceptibility to mPTP opening. Rat cardiac subsarcolemmal (SSM) or interfibrillar (IFM) mitochondrial suspensions exposed directly to rat 18 kDa low molecular weight (Lo-) FGF2 isoform displayed increased resistance to calcium overload-induced mPTP, measured spectrophotometrically as “swelling”, or as cytochrome c release from mitochondria. Inhibition of mitochondrial protein kinase C epsilon abrogated direct Lo-FGF2 mito-protection. Exposure to the rat 23 kDa high molecular weight (Hi) FGF2 isoform promoted cytochrome c release from SSM and IFM under nonstressed conditions. The effect of Hi-FGF2 was prevented by mPTP inhibitors, pre-exposure to Lo-FGF2, and okadaic acid, a serine/threonine phosphatase inhibitor. Western blotting and immunoelectron microscopy pointed to the presence of immunoreactive FGFR1 in cardiac mitochondria in situ. The direct mito-protective effect of Lo-FGF2, as well as the deleterious effect of Hi-FGF2, were prevented by FGFR1 inhibitors and FGFR1 neu-tralizing antibodies. We propose that intracellular FGF2 isoforms can modulate mPTP opening by interacting with mito-FGFR1 and relaying isoform-specific intramitochondrial signal transduction.

AB - Mitochondria, abundant organelles in high energy demand cells such as cardiomyocytes, can determine cell death or survival by regulating the opening of mitochondrial permeability transition pore, mPTP. We addressed the hypothesis that the growth factor FGF2, known to reside in intracellular locations, can directly influence mitochondrial susceptibility to mPTP opening. Rat cardiac subsarcolemmal (SSM) or interfibrillar (IFM) mitochondrial suspensions exposed directly to rat 18 kDa low molecular weight (Lo-) FGF2 isoform displayed increased resistance to calcium overload-induced mPTP, measured spectrophotometrically as “swelling”, or as cytochrome c release from mitochondria. Inhibition of mitochondrial protein kinase C epsilon abrogated direct Lo-FGF2 mito-protection. Exposure to the rat 23 kDa high molecular weight (Hi) FGF2 isoform promoted cytochrome c release from SSM and IFM under nonstressed conditions. The effect of Hi-FGF2 was prevented by mPTP inhibitors, pre-exposure to Lo-FGF2, and okadaic acid, a serine/threonine phosphatase inhibitor. Western blotting and immunoelectron microscopy pointed to the presence of immunoreactive FGFR1 in cardiac mitochondria in situ. The direct mito-protective effect of Lo-FGF2, as well as the deleterious effect of Hi-FGF2, were prevented by FGFR1 inhibitors and FGFR1 neu-tralizing antibodies. We propose that intracellular FGF2 isoforms can modulate mPTP opening by interacting with mito-FGFR1 and relaying isoform-specific intramitochondrial signal transduction.

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A cardiac mitochondrial fgfr1 mediates the antithetical effects of fgf2 isoforms on permeability transition

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

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