A Cardiac Mitochondrial FGFR1 Mediates the Antithetical Effects of FGF2 Isoforms on Permeability Transition.

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

doi:10.3390/cells10102735

Wattamon Srisakuldee, Robert R Fandrich + Show 4 more

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https://doi.org/10.3390/cells10102735

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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 neutralizing antibodies. We propose that intracellular FGF2 isoforms can modulate mPTP opening by interacting with mito-FGFR1 and relaying isoform-specific intramitochondrial signal transduction.

Highlights

Many cardiac pathologies leading to heart failure are intimately linked to mitochondrial dysfunction [1,2]
We have previously shown that calcium-induced mitochondrial swelling, as measured in our experiments, is fully prevented in the presence of the mitochondrial permeability transition pore (mPTP) inhibitor cyclosporine A, Cyclosporin A (CsA) [17]
The main findings presented here are as follows: (i) low molecular weight (Lo-)FGF2 or high molecular weight (Hi)-FGF2 exert, respectively, direct, beneficial, or detrimental effects on isolated cardiac mitochondria; (ii) mitochondria possess a functional FGFR1-like receptor; (iii) mito-FGFR1 relays the beneficial effects of Lo-FGF2 via mito-PKCε activity, and the deleterious effects of Hi-FGF2 via phosphatase 1 (PP1) or phosphatase 2A (PP2A)-type phosphatase(s) activity

Summary

Introduction

Many cardiac pathologies leading to heart failure are intimately linked to mitochondrial dysfunction [1,2]. To maintain their contractile function, cardiomyocytes have high energy demands that are met by their high mitochondrial content. In addition to signal transduction initiated at the plasma membrane level, it is plausible that FGF2 and FGFR1 are engaged in intracellular signalling. Both Loand Hi-FGF2 are capable of activating signaling via FGFR1 [13]

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