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

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2735
Author(s):  
Wattamon Srisakuldee ◽  
Barbara E. Nickel ◽  
Robert R. Fandrich ◽  
Feixong Zhang ◽  
Kishore B. S. Pasumarthi ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Cytochrome C ◽  
Neutralizing Antibodies ◽  
Energy Demand ◽  
Mitochondrial Permeability Transition ◽  
Mitochondrial Protein ◽  
Permeability Transition ◽  
High Energy ◽  
Cytochrome C Release ◽  
Mptp Opening

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.

Effect of chronic contractile activity on SS and IMF mitochondrial apoptotic susceptibility in skeletal muscle

2007 ◽  
Vol 292 (3) ◽  
pp. E748-E755 ◽  
Author(s):  
Peter J. Adhihetty ◽  
Vladimir Ljubicic ◽  
David A. Hood
Keyword(s):  
Skeletal Muscle ◽  
Cytochrome C ◽  
Manganese Superoxide Dismutase ◽  
Mitochondrial Permeability Transition ◽  
Contractile Activity ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Ros Production ◽  
Cytochrome C Release ◽  
Apoptosis Inducing Factor

Chronic contractile activity of skeletal muscle induces an increase in mitochondria located in proximity to the sarcolemma [subsarcolemmal (SS)] and in mitochondria interspersed between the myofibrils [intermyofibrillar (IMF)]. These are energetically favorable metabolic adaptations, but because mitochondria are also involved in apoptosis, we investigated the effect of chronic contractile activity on mitochondrially mediated apoptotic signaling in muscle. We hypothesized that chronic contractile activity would provide protection against mitochondrially mediated apoptosis despite an elevation in the expression of proapoptotic proteins. To induce mitochondrial biogenesis, we chronically stimulated (10 Hz; 3 h/day) rat muscle for 7 days. Chronic contractile activity did not alter the Bax/Bcl-2 ratio, an index of apoptotic susceptibility, and did not affect manganese superoxide dismutase levels. However, contractile activity increased antiapoptotic 70-kDa heat shock protein and apoptosis repressor with a caspase recruitment domain by 1.3- and 1.4-fold ( P < 0.05), respectively. Contractile activity elevated SS mitochondrial reactive oxygen species (ROS) production 1.4- and 1.9-fold ( P < 0.05) during states IV and III respiration, respectively, whereas IMF mitochondrial state IV ROS production was suppressed by 28% ( P < 0.05) and was unaffected during state III respiration. Following stimulation, exogenous ROS treatment produced less cytochrome c release (25–40%) from SS and IMF mitochondria, and also reduced apoptosis-inducing factor release (≈30%) from IMF mitochondria, despite higher inherent cytochrome c and apoptosis-inducing factor expression. Chronic contractile activity did not alter mitochondrial permeability transition pore (mtPTP) components in either subfraction. However, SS mitochondria exhibited a significant increase in the time to Vmax of mtPTP opening. Thus, chronic contractile activity induces predominantly antiapoptotic adaptations in both mitochondrial subfractions. Our data suggest the possibility that chronic contractile activity can exert a protective effect on mitochondrially mediated apoptosis in muscle.

scholarly journals Metformin inhibits mitochondrial permeability transition and cell death: a pharmacological in vitro study

2004 ◽  
Vol 382 (3) ◽  
pp. 877-884 ◽  
Author(s):  
Bruno GUIGAS ◽  
Dominique DETAILLE ◽  
Christiane CHAUVIN ◽  
Cécile BATANDIER ◽  
Frédéric De OLIVEIRA ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytochrome C ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Cytochrome C Release ◽  
Intact Cells ◽  
Human Carcinoma ◽  
Butyl Hydroperoxide ◽  
Mitochondrial Permeability ◽  
New Findings

Metformin, a drug widely used in the treatment of Type II diabetes, has recently received attention owing to new findings regarding its mitochondrial and cellular effects. In the present study, the effects of metformin on respiration, complex 1 activity, mitochondrial permeability transition, cytochrome c release and cell death were investigated in cultured cells from a human carcinoma-derived cell line (KB cells). Metformin significantly decreased respiration both in intact cells and after permeabilization. This was due to a mild and specific inhibition of the respiratory chain complex 1. In addition, metformin prevented to a significant extent mitochondrial permeability transition both in permeabilized cells, as induced by calcium, and in intact cells, as induced by the glutathione-oxidizing agent t-butyl hydroperoxide. This effect was equivalent to that of cyclosporin A, the reference inhibitor. Finally, metformin impaired the t-butyl hydroperoxide-induced cell death, as judged by Trypan Blue exclusion, propidium iodide staining and cytochrome c release. We propose that metformin prevents the permeability transition-related commitment to cell death in relation to its mild inhibitory effect on complex 1, which is responsible for a decreased probability of mitochondrial permeability transition.

scholarly journals Bax-induced Cytochrome C Release from Mitochondria Is Independent of the Permeability Transition Pore but Highly Dependent on Mg2+ Ions

1998 ◽  
Vol 143 (1) ◽  
pp. 217-224 ◽  
Author(s):  
Robert Eskes ◽  
Bruno Antonsson ◽  
Astrid Osen-Sand ◽  
Sylvie Montessuit ◽  
Christoph Richter ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cyclosporin A ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cytochrome C Release ◽  
Mitochondrial Permeability ◽  
Isolated Mitochondria ◽  
Mammalian Homologue

Bcl-2 family members either promote or repress programmed cell death. Bax, a death-promoting member, is a pore-forming, mitochondria-associated protein whose mechanism of action is still unknown. During apoptosis, cytochrome C is released from the mitochondria into the cytosol where it binds to APAF-1, a mammalian homologue of Ced-4, and participates in the activation of caspases. The release of cytochrome C has been postulated to be a consequence of the opening of the mitochondrial permeability transition pore (PTP). We now report that Bax is sufficient to trigger the release of cytochrome C from isolated mitochondria. This pathway is distinct from the previously described calcium-inducible, cyclosporin A–sensitive PTP. Rather, the cytochrome C release induced by Bax is facilitated by Mg2+ and cannot be blocked by PTP inhibitors. These results strongly suggest the existence of two distinct mechanisms leading to cytochrome C release: one stimulated by calcium and inhibited by cyclosporin A, the other Bax dependent, Mg2+ sensitive but cyclosporin insensitive.

Cardiac mitochondrial cGMP stimulates cytochrome c release

2006 ◽  
Vol 112 (2) ◽  
pp. 113-121 ◽  
Author(s):  
Kazuhiko Seya ◽  
Shigeru Motomura ◽  
Ken-Ichi Furukawa
Keyword(s):  
Cytochrome C ◽  
Mitochondrial Permeability Transition ◽  
Mitochondrial Protein ◽  
Left Ventricular ◽  
Cgmp Level ◽  
Dependent Manner ◽  
Cardiac Mitochondria ◽  
Cytochrome C Release ◽  
Independent Manner ◽  
Rat Cardiomyocytes

Although the existence of cardiac mitochondrial cGMP has been reported previously [Kimura and Murad (1974) J. Biol. Chem. 249, 6910–6916], the physiological and pathophysiological properties of cGMP in cardiac mitochondria have remained unknown. The aim of the present study was to clarify whether cardiac mitochondrial cGMP regulates the apoptosis of cardiomyocytes. In the presence of GTP, the NO donors SNAP (S-nitroso-N-acetyl-DL-penicillamine; 1 mmol/l) and SNP (sodium nitroprusside; 1 mmol/l) each markedly increased the cGMP level in a highly purified mitochondrial protein fraction prepared from left ventricular myocytes of male Wistar rats, and these increases were inhibited by 1 μmol/l ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), an inhibitor of NO-sensitive guanylate cyclase. In purified mitochondria, both SNAP (1 mmol/l) and the membrane-permeant cGMP analogue 8-Br-cGMP (8-bromo-cGMP; 1 mmol/l), but not cGMP (1 mmol/l), increased cytochrome c release from succinate-energized mitochondria without inducing mitochondrial swelling and depolarization of the mitochondrial membrane as factors of activation of MPT (mitochondrial permeability transition). The cytochrome c release mediated by SNAP was inhibited in the presence of 1 μmol/l ODQ. On the other hand, 1 mmol/l SNAP induced apoptosis in primary cultured adult rat cardiomyocytes in a time-dependent manner, and this induction was significantly inhibited in the presence of ODQ. Furthermore, apoptosis induced in primary cultured cardiomyocytes by hypoxia/re-oxygenation was also inhibited by ODQ. These results suggest that the acceleration of cGMP production in cardiac mitochondria stimulates cytochrome c release from mitochondria in an MPT-independent manner, resulting in apoptosis.

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