Calcium-induced release of cytochrome c from cardiolipin nanodisks: Implications for apoptosis

Fox, Colin A.; Lethcoe, Kyle; Ryan, Robert O.

doi:10.1016/j.bbamem.2021.183722

Cited by 14 publications

(7 citation statements)

References 45 publications

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“…Hypoxia-induced deterioration of mitochondrial membrane integrity permits the release of cytochrome C, which could be intensified by competitive binding of highly positive Ca 2+ with the highly negative cardiolipin outer surface of the inner mitochondrial membrane. 58,59 This study found a significant increase in cytosolic cytochrome C level, resulting in increased expression of cleaved caspase-3 and amplified activity of caspase 3-7 in hypoxic C2C12 myoblasts. Increased cytochrome C also exaggerates the release of Ca 2+ from the ER to the cytosol by binding to inositol (1,4,5) trisphosphate receptors in the endoplasmic reticulum.…”

Section: Discussionmentioning

confidence: 66%

Mitochondrial Ca²⁺ overload due to altered proteostasis amplifies apoptosis in C2C12 myoblasts under hypoxia: Protective role of nanocurcumin formulation

et al. 2023

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Severe hypoxia triggers apoptosis leads to myofibers loss and is attributable to impaired intracellular calcium (iCa2+) homeostasis, resulting in reduced muscle activity. Hypoxia increases intracellular Ca2+ by activating the release of Ca2+ from iCa2+ stores, however, the effect of increased [iCa2+] on the mitochondria of muscle cells at high‐altitude hypoxia is largely unexplored. This study examined mitochondrial Ca2+ overload due to altered expression of mitochondrial calcium uptake 1 (MICU1), that is, a gatekeeper of the mitochondrial Ca2+ uniporter, impaired mitochondrial membrane potential (ΔΨm). p53 stabilization and its translocation to the mitochondria were observed following disrupted mitochondrial membrane integrity in myoblasts under hypoxia. Furthermore, the downstream effects of p53 led to the upregulation of proapoptotic proteins (Bax, Caspase‐3, and cytochrome C) in myoblasts under hypoxia. Nanocurcumin‐pyrroloquinoline quinone formulation (NCF; Indian patent no. 302877), developed to address hypoxia‐induced consequences, was found to be beneficial in maintaining mitochondrial Ca2+ homeostasis and limiting p53 translocation into mitochondria under hypoxia in muscle myoblasts. NCF treatment also modulates heat shock proteins and apoptosis‐regulating protein expression in myoblasts. Conclusively, we proposed that mitochondrial Ca2+ overload due to altered MICU1 expression intensifies apoptosis and mitochondrial dysfunctionality. The study also reported that NCF could improve mitochondrial [Ca2+] homeostasis and antiapoptotic ability in C2C12 myoblasts under hypoxia.

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Section: Discussionmentioning

confidence: 66%

Mitochondrial Ca²⁺ overload due to altered proteostasis amplifies apoptosis in C2C12 myoblasts under hypoxia: Protective role of nanocurcumin formulation

et al. 2023

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“…Cytochrome C then goes on to activate a signal cascade leading to cellular death. Clearly, mitochondria have an important involvement in some vital cellular functions, meaning its dysfunction is implicated in a large number of diseases, such as cancer, metabolic, neuronal, cardiovascular, or genetic disorders [17,18].…”

Section: Endoplasmic Reticulum and Mitochondriamentioning

confidence: 99%

Endoplasmic Reticulum: A Hub in Lipid Homeostasis

Ventura¹,

Hernández‐Álvarez²

2023

Updates on Endoplasmic Reticulum

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Endoplasmic Reticulum (ER) is the largest and one of the most complex cellular structures, indicating its widespread importance and variety of functions, including synthesis of membrane and secreted proteins, protein folding, calcium storage, and membrane lipid biogenesis. Moreover, the ER is implicated in cholesterol, plasmalogen, phospholipid, and sphingomyelin biosynthesis. Furthermore, the ER is in contact with most cellular organelles, such as mitochondria, peroxisomes, Golgi apparatus, lipid droplets, plasma membrane, etc. Peroxisomes are synthesized from a specific ER section, and they are related to very-long-chain fatty acid metabolism. Similarly, lipid droplets are vital structures in lipid homeostasis that are formed from the ER membrane. Additionally, there is a specific region between the ER-mitochondria interface called Mitochondria-Associated Membranes (MAMs). This small cytosolic gap plays a key role in several crucial mechanisms from autophagosome synthesis to phospholipid transfer. Due to the importance of the ER in a variety of biological processes, alterations in its functionality have relevant implications for multiple diseases. Nowadays, a plethora of pathologies like non-alcoholic steatohepatitis (NASH), cancer, and neurological alterations have been associated with ER malfunctions.

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“…This solution was mixed 1:1 with 2× H 2 O 2 (100 mM) in 50 mM buffer using a stopped-flow instrument yielding a final solution containing 1 μM Cytc, 50 mM H 2 O 2 , and guaiacol at the desired concentration in 50 86,87 Guaiacol concentration was determined spectroscopically (ε 274 = 2150 M −1 cm −1 ). 88 Final guaiacol concentrations were 0, 2,4,6,8,10,15,20,25,30,40,50,60,80, and 100 μM. The segment of the A 470 versus time data with the greatest slope following the initial lag phase was used to obtain initial velocity, ν, at each guaiacol concentration.…”

Section: ■ Experimental Proceduresmentioning

confidence: 99%

“…2,3 Normally, Cytc resides within the cristae of the mitochondria where its main role is in oxidative phosphorylation. 3,4 Upon apoptotic stimuli, Cytc converts from an electron carrier to a peroxidase, enabling Cytc to oxidize cardiolipin (CL). 5 The affinity between oxidized CL and Cytc is drastically reduced, facilitating release of Cytc into the cytosol, where it binds to Apaf-1 to form the apoptosome.…”

Section: ■ Introductionmentioning

confidence: 99%

“…In its native state with Met80 bound to the heme, Cyt c is an efficient electron carrier, shuttling electrons from the cytochrome bc 1 complex to cytochrome c oxidase in oxidative phosphorylation . It also serves as an important mediator of the intrinsic pathway of apoptosis. , Normally, Cyt c resides within the cristae of the mitochondria where its main role is in oxidative phosphorylation. , Upon apoptotic stimuli, Cyt c converts from an electron carrier to a peroxidase, enabling Cyt c to oxidize cardiolipin (CL) . The affinity between oxidized CL and Cyt c is drastically reduced, facilitating release of Cyt c into the cytosol, where it binds to Apaf-1 to form the apoptosome .…”

Section: Introductionmentioning

confidence: 99%

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Alkaline State of the Domain-Swapped Dimer of Human Cytochrome c: A Conformational Switch for Apoptotic Peroxidase Activity

2022

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A 2.08 Å structure of an alkaline conformer of the domain-swapped dimer of K72A human cytochrome c (Cytc) crystallized at pH 9.9 is presented. In the structure, Lys79 is ligated to the heme. All other domain-swapped dimer structures of Cytc have water bound to this coordination site. Part of Ω-loop D (residues 70–85) forms a flexible linker between the subunits in other Cytc domain-swapped dimer structures but instead converts to a helix in the alkaline conformer of the dimer combining with the C-terminal helix to form two 26-residue helices that bracket both sides of the dimer. The alkaline transition of the K72A human dimer monitored at both 625 nm (high spin heme) and 695 nm (Met80 ligation) yields midpoint pH values of 6.6 and 7.6, respectively, showing that the Met80 → Lys79 and high spin to low spin transitions are distinct. The dimer peroxidase activity increases rapidly below pH 7, suggesting that population of the high spin form of the heme is what promotes peroxidase activity. Comparison of the structures of the alkaline dimer and the neutral pH dimer shows that the neutral pH conformer has a better electrostatic surface for binding to a cardiolipin-containing membrane and provides better access for small molecules to the heme iron. Given that the pH of mitochondrial cristae ranges from 6.9 to 7.2, the alkaline transition of the Cytc dimer could provide a conformational switch to tune the peroxidase activity of Cytc that oxygenates cardiolipin in the early stages of apoptosis.

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Calcium-induced release of cytochrome c from cardiolipin nanodisks: Implications for apoptosis

Cited by 14 publications

References 45 publications

Mitochondrial Ca²⁺ overload due to altered proteostasis amplifies apoptosis in C2C12 myoblasts under hypoxia: Protective role of nanocurcumin formulation

Mitochondrial Ca²⁺ overload due to altered proteostasis amplifies apoptosis in C2C12 myoblasts under hypoxia: Protective role of nanocurcumin formulation

Endoplasmic Reticulum: A Hub in Lipid Homeostasis

Alkaline State of the Domain-Swapped Dimer of Human Cytochrome c: A Conformational Switch for Apoptotic Peroxidase Activity

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Calcium-induced release of cytochrome c from cardiolipin nanodisks: Implications for apoptosis

Cited by 14 publications

References 45 publications

Mitochondrial Ca2+ overload due to altered proteostasis amplifies apoptosis in C2C12 myoblasts under hypoxia: Protective role of nanocurcumin formulation

Mitochondrial Ca2+ overload due to altered proteostasis amplifies apoptosis in C2C12 myoblasts under hypoxia: Protective role of nanocurcumin formulation

Endoplasmic Reticulum: A Hub in Lipid Homeostasis

Alkaline State of the Domain-Swapped Dimer of Human Cytochrome c: A Conformational Switch for Apoptotic Peroxidase Activity

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Mitochondrial Ca²⁺ overload due to altered proteostasis amplifies apoptosis in C2C12 myoblasts under hypoxia: Protective role of nanocurcumin formulation

Mitochondrial Ca²⁺ overload due to altered proteostasis amplifies apoptosis in C2C12 myoblasts under hypoxia: Protective role of nanocurcumin formulation