The mitochondrial permeability transition in liver and heart

doi:10.21203/rs.3.rs-2997264/v1

Download PDF

Research Article

The mitochondrial permeability transition in liver and heart

https://doi.org/10.21203/rs.3.rs-2997264/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Opening of the inner mitochondrial membrane (IMM) permeability transition pore (PTP) dissipates ion gradients and the transmembrane electric potential (ΔΨ) across IMM, releasing excess Ca²⁺ from the mitochondrial matrix. Immediate closure of PTP must follow to prevent outer membrane disruption, loss of cytochrome C and eventual apoptosis. Flickering, defined as the rapid alternative opening/closing of PTP, has been reported in heart, which undergoes frequent, large variations in Ca²⁺. In contrast, in tissues that undergo depolarization events less frequently, such as the liver, PTP would not need to be as dynamic and thus these tissues would not be as resistant to stress. To evaluate this idea, it was decided to follow the reversibility of the permeability transition (PT) in isolated mitochondria from two different tissues: the very dynamic heart, and the liver, which suffers depolarizations less frequently. It was observed that in heart mitochondria PT remained reversible for longer periods and at higher Ca²⁺ loads than in liver mitochondria. This was evaluated measuring the rate of oxygen consumption, organelle swelling and Ca²⁺ retention capacity. It is suggested that PTP fitness varies in a tissue-specific manner.

Tissue-specificity

Mitochondrial Permeability Transition

Heart mitochondria

Liver mitochondria

Calcium

In response to different stimuli, large fluctuations in Ca²⁺ concentration are observed both in the cytosol [Ca²⁺]_cyt and in mitochondria [Ca²⁺]_Mit (Campbell, 2014; Carafoli, 1987; Romero-Garcia & Prado-Garcia, 2019) modulating many processes including oxidative phosphorylation (Bagur & Hajnóczky, 2017). The mitochondrial Ca²⁺ uniporter (MCU) transports Ca2 + into the mitochondrial matrix (Kovacs-Bogdan et al., 2014; Vais et al., 2020) while a slower Ca2 + return to the cytoplasm is mediated by antiport with either Na⁺ (in heart) or H⁺ (in liver) (Belosludtsev et al., 2019) In the extracellular compartment Ca²⁺ is 10⁴ times more concentrated than in the cytoplasm and its uptake upon cell stimulation make it an ideal second messenger (Campbell, 2014).

In mitochondria, Ca²⁺ uptake is faster than efflux, so the matrix may become saturated during high cellular activity (Basso et al., 2018; Williams et al., 2013). This seems to be solved by opening the IMM permeability transition pore (PTP). PTP allows passage of molecules up to 1.5 kDa, collapsing the electric transmembrane potential (ΔΨ) and allowing [Ca²⁺]_Mit to diffuse to the cytoplasm (Balakirev & Zimmer, 1998; Haworth & Hunter, 1979; Hurst et al., 2017). In addition to depleting [Ca²⁺]_Mit, PTP opening prevents ROS overproduction (Cadenas, 2018; Morales-García et al., 2021). However, PTP must close rapidly to prevent damage (Kim et al., 2003; Rottenberg & Hoek, 2021). Indeed, irreversible-opening of PTP has been associated to cell death due to external mitochondrial membrane disruption and eventual release into the cytoplasm of proteins such as cytochrome C and the apoptosis-inducing factor (AIF) (Bauer & Murphy, 2020; Crompton, 1999; Kroemer et al., 2007; Petronilli et al., 2001).

From the above, it may be proposed that together with the detoxifying role of PTP opening, its efficient closure is needed for survival. Indeed, flickering has been reported in heart and muscle mitochondria (Boyman et al., 2019; Korge et al., 2011; Lu et al., 2016). Still, it is not known if PTP dynamics differ from tissue to tissue, i.e. whether in tissues that seldom see variations in [Ca²⁺]_Mit, such as the liver (Bagur & Hajnóczky, 2017; Burgess et al., 1984; Carafoli, 1987) PTP is as resilient as in tissues that are subjected to large, frequent Ca²⁺ fluxes such as the heart (Abelmann, 1961; Akopova, 2001; Chalmers & Nicholls, 2003; Zhong et al., 2008). Here, PTP reversibility in isolated mitochondria from either heart or liver was compared to determine whether PTP properties vary from tissue to tissue. Heart mitochondria PT remained reversible for longer periods and under higher concentrations than liver mitochondria.

Reagents. All chemicals used were analytic grade. Sucrose, CaCl₂, succinic acid, pyruvic acid, malic acid, EGTA, ADP, safranine-O and oligomycin were from Sigma Chem Co (St Louis, MO). Bovine serum albumin was from GoldBio (St Louis, MO). H₃PO₄, KCl and MgCl₂ were from J.T. Baker Chemical Co. (Phillipsburg, N. J.).

Animals. Wistar male rats weighing 200 g were obtained from our animal facility at the Instituto de Fisiología Celular (IFC, UNAM) and were housed at 22 ± 2°C on a 12 h/12 h light/dark cycle, with free access to a standard laboratory rodent chow and water. Before the experiment, each rat was fasted for 12 hours and euthanized by decapitation. A local committee approved all experimental procedures according to Ethics in Animal Experimentation (SUV124-19).

Isolation of Mitochondria. Liver and heart tissues from the same individual. were placed in cold isolation buffer (250 mM sucrose, 10 mM Tris–HCl and 1 mM EDTA, pH 7.3). Then hearts were minced and incubated for 10 min in isolation buffer plus 1 mg/ml proteinase K, centrifuged at 3000×g for 10 min and washed with the same buffer before being homogenized. Mitochondria were obtained by differential centrifugation (Correa et al., 2007). To obtain liver mitochondria, the liver was minced in the same isolation buffer. Mitochondria from each tissue were obtained by differential centrifugation and resuspended in reaction buffer (250 mM sucrose, 10 mM Tris, 20 µM EDTA, pH 7.4) (Gutiérrez-Aguilar et al., 2014). Mitochondrial suspensions were kept in an ice bath and used within 3 h. To evaluate mitochondrial quality, oxygen consumption measurements and respiratory control were evaluated, Mitochondria were used only when the respiratory control was at least 4.0 for liver or 6.0 for heart.

Mitochondrial swelling. Swelling was followed as the decrease in absorbance at 540 nm (Jung et al., 1997). We used a DW2000 Olis/Aminco spectrophotometer in split mode. The concentrations of Ca²⁺ and EGTA used are indicated under each figure.

Oxygen consumption. Experiments were conducted using a high-resolution oxygraph (Oroboros, Innsbruck, Austria) at 30°C with continuous magnetic stirring. Mitochondria (1 mg protein per mL) were added to a chamber containing glutamate/malate 1 mM/1 mM. After measuring the basal O₂ consumption, one pulse of Ca²⁺ was added and EGTA was added at different times. Where indicated, ADP 300 µM was added to evaluate oxidative phosphorylation (OXPHOS).

Determination of mitochondrial Ca ²⁺ retention capacity. Measurements of mitochondrial Ca²⁺ retention capacity in suspensions of intact mitochondria (1 mg protein per mL) were performed at room temperature with continuous magnetic stirring in a DW2000 Olis/Aminco spectrophotometer in dual mode 675–685 nm. A standard reaction medium (250 mM sucrose,, 5 mM KH₂PO₄, 10 mM HEPES buffer with pH adjusted to 7.4 with KOH) was supplemented with 50 µM Arsenazo-III, 100 µM ADP, and NADH-linked respiratory substrates (1 mM malate, 2.5 mM glutamate). Ca²⁺ was added in pulses 5 or 10 µM each 1.5 min (Petronilli et al., 1993; Scarpa & Azzi, 1968).

Statistical analysis. Two-tailed unpaired Student’s t-tests were performed. Data are presented as mean ± S.D. Sample sizes are indicated in figure captions. Tests were considered significant at the 95% level of confidence (P < 0.05). GraphPad Prism 8 (GraphPad Software, San Diego, CA, USA) was used for statistical analysis and to draw graphs.

To compare mitochondrial PT sensitivity and reversibility in two different tissues from the same subject, different physiological parameters were measured in mitochondria isolated from either liver or heart.

Oxygen consumption

Different reports indicate that in mitochondria, Ca²⁺ addition increases the rate of O₂ consumption and then, if Ca²⁺ transport stops, the rate of O₂ consumption returns to a basal level, unless PT is triggered (Batandier et al., 2004; Zhong et al., 2008). As expected, an increase in the rate of oxygen consumption was observed upon Ca²⁺ addition (Fig. 1). Then, when EGTA was added the return to basal levels was evaluated. In liver mitochondria, 30 µM Ca²⁺ increased the rate of O₂ uptake. Then EGTA addition reverted the increase the rate of O₂ consumption at 30 sec but was ineffective at 60 sec or later (Fig. 1A). These results suggest that liver mitochondrial PT became irreversible at some point after 30 sec. When the same experiment was conducted in heart mitochondria, the same 30 µM Ca²⁺ was added no effects on the rate of O₂ consumption were observed and EGTA had no further effects (Fig. 1B two upper traces). Raising added Ca²⁺ to 150 µM did increase the rate of O₂ consumption, although this reverted to the basal rate in all cases and EGTA addition had no further effects (Fig. 2B two lower traces). Thus, in liver mitochondria PT was triggered sometime between 30 and 60 sec, while in the heart no PT was observed even after 180 sec. These results suggest that heart mitochondria PTP is much more resistant to Ca²⁺ loading than liver PTP.

Ca ²⁺ driven mitochondrial Swelling. Ca²⁺ is taken avidly by mitochondria (Carafoli; Halestrap & Davidson, 1990) and in the presence of high KCl PT evokes swelling, which can be observed spectrophotometrically (Jung et al., 1997). Thus, to evaluate PT, Ca²⁺ was added to mitochondria in the presence of 20 mM KCl. Liver mitochondria did not swell spontaneously (Fig. 2A trace a). However. sequential 5 µM Ca²⁺ additions led to rapid swelling beginning at the third addition (Fig. 2A trace b). In the presence of cyclosporine A (CsA) swelling was inhibited partially (Fig. 2A trace c) suggesting that swelling was due to PT. Swelling was also minimal in control heart mitochondria (Fig. 2B trace a). Under these conditions repeated addition of 10 µM Ca²⁺ induced mitochondrial swelling (Fig. 2, trace b). Again, CsA inhibited heart mitochondria swelling (Fig. 2B trace c). Thus, the results in Fig. 2 confirm that mitochondrial swelling was more evident and occurred at lower Ca²⁺ concentrations in liver than in heart mitochondria, also cardiac mitochondria did not undergo full swelling (See Fig. 3B).

Reversibility of Ca ²⁺ -driven mitochondrial PTP opening. At high KCl, mitochondria exhibit only a mild rate of swelling (Fig. 3 traces a) unless an adequate amount of Ca²⁺ is added to drive rapid mitochondrial swelling (Fig. 3 traces b). CsA prevents the Ca²⁺ effect, indicating that swelling is due to opening of PTP (Fig. 3 traces c). Then, quenching of Ca²⁺ should stop swelling as soon as PTP closes. This system was in liver and heart mitochondria to explore PT reversibility (Fig. 3). In liver mitochondria full swelling was observed at 30 µM Ca²⁺ while heart mitochondria needed 150 µM Ca²⁺.

In liver mitochondria cyclosporine-sensitive Ca²⁺-mediated mitochondrial swelling was triggered with 30 µM Ca²⁺ (Fig. 3A trace b). Then, EGTA was added at different times and it was observed that swelling stopped at 30 sec (Fig. 3A trace d). When EGTA was added at 60 sec (Fig. 3A trace e) swelling continued for 5 sec and then stopped. Lastly, at 120 sec (Fig. 3A trace f) swelling was not inhibited. When the same experiment was conducted in

heart mitochondria, 150 µM Ca²⁺ was needed to trigger similar swelling (Fig. 3B trace b). In addition, at all times evaluated, 30, 60 or 180 sec EGTA stopped swelling immediately (Fig. 3B traces d, e and f). In addition, while hepatic mitochondrial PTP opening lost reversibility after 30 sec, cardiac mitochondrial PTP remained reversible after all three times evaluated.

Ca ²⁺ -retention assays. As expected from Figs. 2 & 3, in liver mitochondria the fourth to fifth 5 µM Ca²⁺ addition triggered PT and the release for Ca²⁺ (Fig. 4A trace a) CsA delayed PT to about twice the additions (Fig. 4A trace b). In contrast, in heart mitochondria repeatedly adding 5 µM Ca²⁺ with or without CsA did not trigger PT (Fig. 4B). Only when repeatedly adding 20 µM and 30 µM Ca²⁺ PTP opened at 100 mM Ca²⁺. In addition, CsA delayed PT, even when 300 µM Ca²⁺ (Fig. 4C trace b). Again, our results indicate that PTP in heart mitochondria withstands much higher tearing than liver mitochondria and it remains reversible for much longer.

In addition to releasing ions from the matrix, PTP has been proposed to work as a physiological uncoupling mechanism that prevents mitochondrial ROS over-production (Morales-García et al., 2021). Here, in liver mitochondria PTP opening did not affect ROS concentration, but instead, after 2 to 4 min ROS increased slightly as compared to the control (Fig. 5A). In contrast, in heart mitochondria PTP opening decreased a small percentage of ROS (Fig. 5B). Further experiments are needed to determine whether in the heart PTP opening decreased ROS production is significative.

In human heart myocytes, Ca²⁺ floods the cytoplasm 72 to 80 times per minute and during intense cardiac activity beats may increase to 160/min (Cheng & Lederer, 2008). Under these conditions, Ca²⁺ saturates the mitochondrial matrix. To empty matrix Ca²⁺, PTP opens and depolarizes the membrane. Then, PTP needs to be rapidly closed in order to avoid ATP depletion, MEM-disruption, Cytochrome C release and eventually, cell death (Kim et al., 2003; Morciano et al., 2021).

In contrast, organs such as the liver are not subjected to these frequent depolarizations. Sometimes these tissues substitute Ca²⁺ uptake as second messenger using cAMP-dependent signaling (Rodgers, 2022; Wahlang et al., 2018), so mitochondrial Ca²⁺ overload seems to be less likely, i.e. liver mitochondria face lower risk of Ca²⁺ flooding and thus PTP does not need to be as dynamic. To evaluate this idea, it was decided to compare the robustness of the mitochondrial-PTP from liver versus that from heart.

When PTP behavior was compared in mitochondria isolated from liver or from heart, reversibility of PTP opening was lost earlier and with less Ca²⁺ in the liver, as 30 µM Ca²⁺ opened PTP, increasing the rate of oxygen consumption in state 4 (Fig. 1A) and inducing mitochondrial swelling (Figs. 2A and 3A). In fact, a limited ability of liver mitochondria to reverse PT correlated with increased ROS production (Fig. 4A) and may be related to liver disease (Cichoz-Lach & Michalak, 2014; Tang et al., 2022; Zhong et al., 2008). Heart mitochondrial PTP retained reversibility under all parameters evaluated. (Fig. B, 1 to 4).

Ca²⁺ retention and mitochondrial swelling assays showed that even though both mitochondria are capable of loading Ca²⁺ into the matrix (Belosludtsev et al., 2020; Coll et al., 1982; Crompton et al., 1987), the capacity of heart mitochondria is greater (Fig. 4B) as compared to liver mitochondria (Fig. 4A). This is in agreement with reports indicating that heart mitochondrial PTP withstands as much as 250 µM Ca²⁺ before opening (Azzolin et al., 2010; Halestrap, 2004; Korge et al., 2011) while liver mitochondrial PTP opens at 650 nM of Ca²⁺ (Belosludtsev et al., 2020; Chalmers & Nicholls, 2003).

Reversibility of the permeability transition (PT) is vital as the drop in ΔΨ leads to depletion of ATP and external mitochondrial membrane disruption (Kim et al., 2003), which in turn leads to cell death. In liver mitochondria, PT reversibility was lost sometime after 30 sec (Fig. 3A) or three sequential additions of 5 µM Ca²⁺ (Fig. 4A). In contrast in heart mitochondria PT remained reversible for at least 2 min (Fig. 3B) and withstood as much as eight consecutive 20 µM Ca²⁺ additions (Fig. 4B & C). These experiments clearly show that PTP is much more resistant to Ca²⁺ in heart than in liver mitochondria.

In regard to ROS, in heart mitochondria PT led to a slight decrease in ROS production, while PT in liver mitochondria did not affect ROS production. This points to an important role of PT in cardiac physiology, which may not be present in the liver. Also, the mitochondrial network and mitochondrial dynamics are different in both tissues, which could be an important factor explain this (Chojnacki et al., 2023)

It is suggested that PTP function/regulation is tissue-specific. In the heart, it may work as a physiological uncoupling system that detoxifies Ca²⁺ and decreases ROS production. This has been described in the yeast S. cerevisiae (Cabrera-Orefice et al., 2015; Guerrero-Castillo et al., 2012; Morales-García et al., 2021). The physiologic or structural basis for the difference in PTP behavior observed in each tissue is an interesting idea that complements data of PTP regulation and function among species across the tree of life (Azzolin et al., 2010; Frigo et al., 2023). It would be interesting to explore if the frequent depolarization observed in cardiac myocytes favors association of proteins such as the Ca²⁺ uniporter, the ANC, the F₁F_O-ATPase and possibly others while in other tissues in the same organism associations are different or non-existent. In this regard, at least the Ca²⁺ antiport-driven efflux is different in heart where the counter-ion is H⁺ than in the liver where it is Na⁺ (Carafoli, 1987).

AUTHOR CONTRIBUTIONS

Conceptualization, SUC, Experimental design and work CRG, OMR, PCT & MRB, Writing and editing SUC, CRG & MRB, Funding SUC.

FUNDING

This research was partially funded by Grants to SUC: Dirección General de Asuntos del Personal/Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica, Universidad Nacional Autónoma de México, Project IN208821 and Consejo Nacional de Humanidades, Ciencia y Tecnología, CF-2023-I-199.

ACKNOWLEDGMENTS

Dr Natalia Chiquete-Félix and MSc Natalia Copitin provided technical assistance. Dr. Angélica Ruíz-Ramírez participated in discussions and critically read the manuscript. CRG. is a student at the Programa de Doctorado en Ciencias Bioquímicas at Universidad Nacional Autónoma de México (UNAM). MRB. is a student of QFB at Facultad de Química, UNAM. CRG (CVU 966402), MRB (CVU 1202206), PCT (CVU 708685) are CONAHCyT fellows. OMR (CVU 639365) is a postdoctoral fellow funded by CONAHCyT.

Abelmann WH (1961) Cirrhosis of the Liver and Decreased Arterial Oxygen Saturation. Arch Intern Med 108(1):34. https://doi.org/10.1001/archinte.1961.03620070036005
Akopova Ov (2001) Calcium release from the rat liver mitochondria under collapse of the membrane potential. https://www.researchgate.net/publication/7213416
Azzolin L, von Stockum S, Basso E, Petronilli V, Forte MA, Bernardi P (2010) The mitochondrial permeability transition from yeast to mammals. FEBS Lett 584(12):2504–2509. https://doi.org/10.1016/j.febslet.2010.04.023
Bagur R, Hajnóczky G (2017) Intracellular Ca 2 + Sensing: Its Role in Calcium Homeostasis and Signaling. Mol Cell 66(6):780–788. https://doi.org/10.1016/j.molcel.2017.05.028
Balakirev MY, Zimmer G (1998) Gradual Changes in Permeability of Inner Mitochondrial Membrane Precede the Mitochondrial Permeability Transition. Arch Biochem Biophys 356(1):46–54. https://doi.org/10.1006/abbi.1998.0738
Basso E, Rigotto G, Zucchetti AE, Pozzan T (2018) Slow activation of fast mitochondrial Ca2 + uptake by cytosolic Ca2+. J Biol Chem 293(44):17081–17094. https://doi.org/10.1074/jbc.RA118.002332
Batandier C, Leverve X, Fontaine E (2004) Opening of the Mitochondrial Permeability Transition Pore Induces Reactive Oxygen Species Production at the Level of the Respiratory Chain Complex I *. J Biol Chem 279(17):17197–17204. https://doi.org/10.1074/JBC.M310329200
Bauer TM, Murphy E (2020) Role of Mitochondrial Calcium and the Permeability Transition Pore in Regulating Cell Death. Circul Res 126:280–293. https://doi.org/10.1161/CIRCRESAHA.119.316306
Belosludtsev KN, Dubinin Mv, Belosludtseva Nv, Mironova GD (2019) Mitochondrial Ca2 + Transport: Mechanisms, Molecular Structures, and Role in Cells. Biochem (Moscow) 84(6):593–607. https://doi.org/10.1134/S0006297919060026
Belosludtsev KN, Dubinin MV, Talanov EY, Starinets VS, Tenkov KS, Zakharova NM, Belosludtseva NV (2020) Transport of ca2 + and ca2+-dependent permeability transition in the liver and heart mitochondria of rats with different tolerance to acute hypoxia. Biomolecules 10(1). https://doi.org/10.3390/biom10010114
Boyman L, Coleman AK, Zhao G, Wescott AP, Joca HC, Greiser BM, Karbowski M, Ward CW, Lederer WJ (2019) Dynamics of the mitochondrial permeability transition pore: Transient and permanent opening events. Arch Biochem Biophys 666:31–39. https://doi.org/10.1016/j.abb.2019.03.016
Burgess GM, Godfrey PP, McKinney JS, Berridge MJ, Irvine RF, Putney JW (1984) The second messenger linking receptor activation to internal Ca release in liver. Nat 1984 309(5963):63–66. https://doi.org/10.1038/309063a0. 309
Cabrera-Orefice A, Ibarra-García-Padilla R, Maldonado-Guzmán R, Guerrero-Castillo S, Luévano-Martínez LA, Pérez-Vázquez V, Gutiérrez-Aguilar M, Uribe-Carvajal S (2015) The Saccharomyces cerevisiae mitochondrial unselective channel behaves as a physiological uncoupling system regulated by Ca2+, Mg2+, phosphate and ATP. J Bioenerg Biomembr 47(6):477–491. https://doi.org/10.1007/s10863-015-9632-x
Cadenas S (2018) Bioenergetics Mitochondrial uncoupling, ROS generation and cardioprotection. BBA - Bioenergetics 1859(9):940–950. https://doi.org/10.1016/j.bbabio.2018.05.019
Campbell AK (2014) Intracellular Calcium. Intracell Calcium 1:1–789. https://doi.org/10.1002/9781118675410
Carafoli E (1987) Intracellular Calcium Homeostasis. Annu Rev Biochem 56(1):395–433. https://doi.org/10.1146/annurev.bi.56.070187.002143
Chalmers S, Nicholls DG (2003) The relationship between free and total calcium concentrations in the matrix of liver and brain mitochondria. J Biol Chem 278(21):19062–19070. https://doi.org/10.1074/JBC.M212661200
Cheng H, Lederer WJ (2008) Calcium sparks. Physiol Rev 88(4):1491–1545. https://doi.org/10.1152/physrev.00030.2007
Chojnacki AK, Krishnan N, Jijon S, Shutt H, Colarusso TE, P., McKay DM (2023) Tissue imaging reveals disruption of epithelial mitochondrial networks and loss of mitochondria-associated cytochrome-C in inflamed human and murine colon. Mitochondrion, 68(October 2022), 44–59. https://doi.org/10.1016/j.mito.2022.10.004
Cichoz-Lach H, Michalak A (2014) Oxidative stress as a crucial factor in liver diseases. World J Gastroenterol 20(25):8082–8091. https://doi.org/10.3748/wjg.v20.i25.8082
Correa F, Soto V, Zazueta C (2007) Mitochondrial permeability transition relevance for apoptotic triggering in the post-ischemic heart. Int J Biochem Cell Biology 39(4):787–798. https://doi.org/10.1016/j.biocel.2007.01.013
Crompton M (1999) The mitochondrial permeabitity transition pore and its role in cell death. Biochem J 341(2):233–249. https://doi.org/10.1042/0264-6021:3410233
Frigo E, Tommasin L, Lippe G, Carraro M, Bernardi P (2023) The Haves and Have-Nots: The Mitochondrial Permeability Transition Pore across Species. Cells 12(10):1409. https://doi.org/10.3390/cells12101409
Guerrero-Castillo S, Cabrera-Orefice A, Vázquez-Acevedo M, González-Halphen D, Uribe-Carvajal S (2012) During the stationary growth phase, Yarrowia lipolytica prevents the overproduction of reactive oxygen species by activating an uncoupled mitochondrial respiratory pathway. Biochim et Biophys Acta (BBA) - Bioenergetics 1817(2):353–362. https://doi.org/10.1016/J.BBABIO.2011.11.007
Gutiérrez-Aguilar M, Douglas DL, Gibson AK, Domeier TL, Molkentin JD, Baines CP (2014) Genetic manipulation of the cardiac mitochondrial phosphate carrier does not affect permeability transition. J Mol Cell Cardiol 72:316–325. https://doi.org/10.1016/j.yjmcc.2014.04.008
Halestrap AP (2004) Mitochondrial permeability: dual role for the ADP/ATP translocator? Nature 430(7003):626–629. https://doi.org/10.1038/nature02816
Haworth RA, Hunter DR (1979) The Ca2+-induced membrane transition in mitochondria. Arch Biochem Biophys 195(2):460–467. https://doi.org/10.1016/0003-9861(79)90372-2
Hurst S, Hoek J, Sheu S-S (2017) Mitochondrial Ca2 + and regulation of the permeability transition pore. J Bioenerg Biomembr 49(1):27–47. https://doi.org/10.1007/s10863-016-9672-x
Jung DW, Bradshaw PC, Pfeiffer DR (1997) Properties of a Cyclosporin-insensitive Permeability Transition Pore in Yeast Mitochondria. J Biol Chem 272(34):21104–21112. https://doi.org/10.1074/jbc.272.34.21104
Kim J-S, He L, Lemasters JJ (2003) Mitochondrial permeability transition: a common pathway to necrosis and apoptosis. Biochem Biophys Res Commun 304(3):463–470. https://doi.org/10.1016/S0006-291X(03)00618-1
Korge P, Yang L, Yang JH, Wang Y, Qu Z, Weiss JN (2011) Protective role of transient pore openings in calcium handling by cardiac mitochondria. J Biol Chem 286(40):34851–34857. https://doi.org/10.1074/jbc.M111.239921
Kovacs-Bogdan E, Sancak Y, Kamer KJ, Plovanich M, Jambhekar A, Huber RJ, Myre MA, Blower MD, Mootha VK (2014) Reconstitution of the mitochondrial calcium uniporter in yeast. Proceedings of the National Academy of Sciences, 111(24), 8985–8990. https://doi.org/10.1073/pnas.1400514111
Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial membrane permeabilization in cell death. Physiol Rev 87(1):99–163. https://doi.org/10.1152/physrev.00013.2006
Lu X, Kwong JQ, Molkentin JD, Bers DM (2016) Individual cardiac mitochondria undergo rare transient permeability transition pore openings. Circul Res 118(5):834–841. https://doi.org/10.1161/CIRCRESAHA.115.308093
Morales-García L, Ricardez-García C, Castañeda-Tamez P, Chiquete-Félix N, Uribe-Carvajal S (2021) Coupling/Uncoupling Reversibility in Isolated Mitochondria from Saccharomyces cerevisiae. Life 11(12):1307. https://doi.org/10.3390/life11121307
Morciano G, Naumova N, Koprowski P, Valente S, Sardão VA, Potes Y, Rimessi A, Wieckowski MR, Oliveira PJ (2021) The mitochondrial permeability transition pore: an evolving concept critical for cell life and death. Biological Reviews, 3. https://doi.org/10.1111/brv.12764
Petronilli V, Cola C, Bernardi P (1993) Modulation of the mitochondrial cyclosporin A-sensitive permeability transition pore. II. The minimal requirements for pore induction underscore a key role for transmembrane electrical potential, matrix pH, and matrix Ca2+. J Biol Chem 268(2):1011–1016. https://doi.org/10.1016/s0021-9258(18)54034-5
Petronilli V, Penzo D, Scorrano L, Bernardi P, Di Lisa F (2001) The mitochondrial permeability transition, release of cytochrome c and cell death. Correlation with the duration of pore openings in situ. J Biol Chem 276(15):12030–12034. https://doi.org/10.1074/jbc.M010604200
Rodgers RL (2022) Glucagon, cyclic AMP, and hepatic glucose mobilization: A half-century of uncertainty. Physiological Rep 10(9). https://doi.org/10.14814/phy2.15263
Romero-Garcia S, Prado-Garcia H (2019) Mitochondrial calcium: Transport and modulation of cellular processes in homeostasis and cancer (Review). Int J Oncol 54(4):1155–1167. https://doi.org/10.3892/ijo.2019.4696
Rottenberg H, Hoek JB (2021) The Mitochondrial Permeability Transition: Nexus of Aging. Disease and Longevity Cells 10(1):79. https://doi.org/10.3390/cells10010079
Scarpa A, Azzi A (1968) Cation binding to submitochondrial particles. Biochim et Biophys Acta (BBA) - Biomembr 150(3):473–481. https://doi.org/10.1016/0005-2736(68)90147-8
Tang SP, Mao XL, Chen YH, Yan LL, Ye LP, Li SW (2022) Reactive Oxygen Species Induce Fatty Liver and Ischemia-Reperfusion Injury by Promoting Inflammation and Cell Death. Front Immunol 13(April):1–13. https://doi.org/10.3389/fimmu.2022.870239
Vais H, Payne R, Paudel U, Li C, Foskett JK (2020) Coupled transmembrane mechanisms control MCU-mediated mitochondrial Ca 2 + uptake. Proceedings of the National Academy of Sciences, 117(35), 21731–21739. https://doi.org/10.1073/pnas.2005976117
Wahlang B, McClain C, Barve S, Gobejishvili L (2018) Role of cAMP and phosphodiesterase signaling in liver health and disease. Cell Signal 49(3):105–115. https://doi.org/10.1016/j.cellsig.2018.06.005
Williams GSB, Boyman L, Chikando AC, Khairallah RJ, Lederer WJ (2013) Mitochondrial calcium uptake. Proc Natl Acad Sci USA 110(26):10479–10486. https://doi.org/10.1073/pnas.1300410110
Zhong Z, Ramshesh VK, Rehman H, Currin RT, Sridharan V, Theruvath TP, Kim I, Wright GL, Lemasters JJ (2008) Activation of the oxygen-sensing signal cascade prevents mitochondrial injury after mouse liver ischemia-reperfusion. Am J Physiol Gastro-Intest Liver Physiol 295:823–832. https://doi.org/10.1152/ajpgi.90287.2008.-The

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

The mitochondrial permeability transition in liver and heart

Status:

Version 1

Abstract

Figures

Introduction

Materials and methods

Results

Discussion

Declarations

References

Additional Declarations

Status:

Version 1