Cytochrome c phosphorylation: Control of mitochondrial electron transport chain flux and apoptosis

Kalpage, Hasini A.; Wan, Junmei; Morse, Paul T.; Zurek, Matthew P.; Turner, Alice A.; Khobeir, Antoine; Yazdi, Nabil; Hakim, Lara; Liu, Jenney; Vaishnav, Asmita; Sanderson, Thomas H.; Recanati, Maurice-Andre; Grossman, Lawrence I.; Lee, Icksoo; Edwards, Brian F.P.; Hüttemann, Maik

doi:10.1016/j.biocel.2020.105704

Cited by 129 publications

(100 citation statements)

References 93 publications

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“…The effect on intact cell respiration observed in the presence of S47E Cyt c was similar to the decrease in COX activity reported in vitro with a Clark-type oxygen electrode [ 12 ] ( Table 1 ). The observation that the rate of the ETC flux could be modulated by modifications of Cyt c further supported our model that the reaction between Cyt c and COX can serve as the rate-limiting step of the ETC controlling overall ETC flux [ 2 ]. In addition, there is evidence that the S47 residue of Cyt c may also interact with the bc 1 complex [ 44 ].…”

Section: Discussionsupporting

confidence: 73%

“…It functions at the intersection between cellular respiration and intrinsic apoptosis, linking the two pathways. Cyt c plays a role in cellular respiration by functioning as the electron carrier between complex III and complex IV (cytochrome c oxidase, COX) in the mitochondrial electron transport chain (ETC) [ 1 , 2 ]. In contrast, the release of Cyt c from the mitochondria into the cytosol is considered the committing step for intrinsic apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to respiration and apoptosis, Cyt c has multiple other cellular functions, such as reactive oxygen species (ROS) scavenging, cardiolipin peroxidase activity, redox-coupled protein import, and ROS formation via the p66Shc protein [ 1 , 5 ]. The COX-catalyzed electron transfer from Cyt c to oxygen is the proposed rate-limiting step of the ETC [ 2 , 6 , 7 ]. Therefore, the functions of Cyt c are tightly regulated by all major regulatory mechanisms, such as allosteric regulation by ATP, expression of tissue-specific isoforms, and reversible post-translational modifications (PTMs), of which phosphorylations are physiologically most relevant [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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Brain-Specific Serine-47 Modification of Cytochrome c Regulates Cytochrome c Oxidase Activity Attenuating ROS Production and Cell Death: Implications for Ischemia/Reperfusion Injury and Akt Signaling

Kalpage

Wan

Morse

et al. 2020

Cells

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We previously reported that serine-47 (S47) phosphorylation of cytochrome c (Cytc) in the brain results in lower cytochrome c oxidase (COX) activity and caspase-3 activity in vitro. We here analyze the effect of S47 modification in fibroblast cell lines stably expressing S47E phosphomimetic Cytc, unphosphorylated WT, or S47A Cytc. Our results show that S47E Cytc results in partial inhibition of mitochondrial respiration corresponding with lower mitochondrial membrane potentials (ΔΨm) and reduced reactive oxygen species (ROS) production. When exposed to an oxygen-glucose deprivation/reoxygenation (OGD/R) model simulating ischemia/reperfusion injury, the Cytc S47E phosphomimetic cell line showed minimal ROS generation compared to the unphosphorylated WT Cytc cell line that generated high levels of ROS upon reoxygenation. Consequently, the S47E Cytc cell line also resulted in significantly lower cell death upon exposure to OGD/R, confirming the cytoprotective role of S47 phosphorylation of Cytc. S47E Cytc also resulted in lower cell death upon H2O2 treatment. Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain. Akt inhibitor wortmannin abolished S47 phosphorylation of Cytc, while the Akt activator SC79 maintained S47 phosphorylation of Cytc. Overall, our results suggest that loss of S47 phosphorylation of Cytc during brain ischemia drives reperfusion injury through maximal electron transport chain flux, ΔΨm hyperpolarization, and ROS-triggered cell death.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Brain-Specific Serine-47 Modification of Cytochrome c Regulates Cytochrome c Oxidase Activity Attenuating ROS Production and Cell Death: Implications for Ischemia/Reperfusion Injury and Akt Signaling

Kalpage

Wan

Morse

et al. 2020

Cells

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“…Apoptosis, or programmed cell death, is systematically regulated by numerous genes involving the pro-and anti-apoptotic families [32]. The mitochondrial pathway, the major apoptosis-inducing pathway, is initiated by releasing cytochrome c (Cyt c) into the cellular cytoplasm to form the apoptosome resulting in activating downstream effector caspase-3 [33]. The balance between pro-apoptotic (Bax) and anti-apoptotic (bcl-2) protein of the Bcl-2 family, both residing in the outer mitochondrial membrane, plays a crucial role on the process of apoptosis by regulating Cyt c release [34].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Cypher induces apoptosis in cardiomyocytes via Akt/p38 MAPK signaling pathway

Xuan

Wang

et al. 2020

Int. J. Med. Sci.

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Background: Dilated cardiomyopathy (DCM) is considered as the most common form of non-ischemic cardiomyopathy with a high mortality worldwide. Cytoskeleton protein Cypher plays an important role in maintaining cardiac function. Genetic studies in human and animal models revealed that Cypher is involved in the development of DCM. However, the underlying molecular mechanism is not fully understood. Accumulating evidences suggest that apoptosis in myocytes may contribute to DCM. Thus, the purpose of this study is to define whether lack of Cypher in cardiomyocytes can elevate apoptosis signaling and lead to DCM eventually. Methods and Results: Cypher-siRNA sufficiently inhibited Cypher expression in cardiomyocytes. TUNEL-positive cardiomyocytes were increased in both Cypher knockdown neonatal rat cardiomyocytes and Cypher knockout mice hearts, which were rare in the control group. Flow cytometry further confirmed that downregulation of Cypher significantly increased myocytes apoptosis in vitro. Cell counting kit-8 assay revealed that Cypher knockdown in H9c2 cells significantly reduced cell viability. Cypher knockdown was found to increase cleaved caspase-3 expression and suppress p21, ratio of bcl-2 to Bax. Cypher-deficiency induced apoptosis was linked to downregulation of Akt activation and elevated p-p38 MAPK accumulation. Pharmacological activation of Akt with SC79 attenuated apoptosis with enhanced phosphorylation of Akt and reduced p-p38 MAPK and Bax expression. Conclusions: Downregulation of Cypher participates in the promotion of cardiomyocytes apoptosis through inhibiting Akt dependent pathway and enhancing p38 MAPK phosphorylation. These findings may provide a new potential therapeutic strategy for the treatment of DCM.

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“…Modification of Cytochrome c. Protein PTM regulate tightly controlled cellular processes and increase the functional diversity of proteins, often acting as a cell response switch. Several post-translational modifications modulate Cc structure and functionality, such as sulfoxidation [187], carbonylation [152], homocysteinylation [188], nitration [179,180], and phosphorylation [189] (Figure 5). Phosphorylation of tyrosine residues is associated with many human pathologies including cancer, ischemia, asthma, and sepsis.…”

Section: Control Of Cardiolipin Oxidation By Post-translationalmentioning

confidence: 99%

Wheel and Deal in the Mitochondrial Inner Membranes: The Tale of Cytochromecand Cardiolipin

Díaz-Quintana

Pérez‐Mejías

Guerra‐Castellano

et al. 2020

Oxidative Medicine and Cellular Longevity

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Cardiolipin oxidation and degradation by different factors under severe cell stress serve as a trigger for genetically encoded cell death programs. In this context, the interplay between cardiolipin and another mitochondrial factor—cytochrome c—is a key process in the early stages of apoptosis, and it is a matter of intense research. Cytochrome c interacts with lipid membranes by electrostatic interactions, hydrogen bonds, and hydrophobic effects. Experimental conditions (including pH, lipid composition, and post-translational modifications) determine which specific amino acid residues are involved in the interaction and influence the heme iron coordination state. In fact, up to four binding sites (A, C, N, and L), driven by different interactions, have been reported. Nevertheless, key aspects of the mechanism for cardiolipin oxidation by the hemeprotein are well established. First, cytochrome c acts as a pseudoperoxidase, a process orchestrated by tyrosine residues which are crucial for peroxygenase activity and sensitivity towards oxidation caused by protein self-degradation. Second, flexibility of two weakest folding units of the hemeprotein correlates with its peroxidase activity and the stability of the iron coordination sphere. Third, the diversity of the mode of interaction parallels a broad diversity in the specific reaction pathway. Thus, current knowledge has already enabled the design of novel drugs designed to successfully inhibit cardiolipin oxidation.

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Cytochrome c phosphorylation: Control of mitochondrial electron transport chain flux and apoptosis

Cited by 129 publications

References 93 publications

Brain-Specific Serine-47 Modification of Cytochrome c Regulates Cytochrome c Oxidase Activity Attenuating ROS Production and Cell Death: Implications for Ischemia/Reperfusion Injury and Akt Signaling

Brain-Specific Serine-47 Modification of Cytochrome c Regulates Cytochrome c Oxidase Activity Attenuating ROS Production and Cell Death: Implications for Ischemia/Reperfusion Injury and Akt Signaling

Downregulation of Cypher induces apoptosis in cardiomyocytes via Akt/p38 MAPK signaling pathway

Wheel and Deal in the Mitochondrial Inner Membranes: The Tale of Cytochromecand Cardiolipin

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