Mutations of cytochrome c identified in patients with thrombocytopenia THC4 affect both apoptosis and cellular bioenergetics

Rocco, Daniela De; Cerqua, Cristina; Goffrini, P; Russo, Giovanna; Pastore, Annalisa; Meloni, Francesca; Nicchia, Elena; Moraes, Carlos T.; Pecci, Alessandro; Salviati, Leonardo; Savoia, Anna

doi:10.1016/j.bbadis.2013.12.002

Cited by 72 publications

(111 citation statements)

References 16 publications

Supporting

Mentioning

103

Contrasting

Unclassified

Order By: Relevance

“…The thrombocytopenia phenotype associated with proapoptotic cytochrome c mutations [1,2] suggests that cytochrome c mediated caspase activation may be essential for platelet formation in humans. To investigate the molecular basis of Thrombocytopenia Cargeeg we generated a knock-in mouse expressing mouse G41S cytochrome c in place of mouse somatic cytochrome c .…”

Section: Resultsmentioning

confidence: 99%

“…In contrast de Rocco et al . reported that Cycs -/- / Cyct -/- mouse lung fibroblasts expressing mouse G41S cytochrome c were significantly more sensitive to activation of the intrinsic apoptosis pathway compared to Cycs -/- / Cyct -/- mouse lung fibroblasts expressing WT mouse cytochrome c [2]. The reason for the discrepancy between the results with recombinant protein and transduced cell lines is unclear.…”

Section: Resultsmentioning

confidence: 99%

“…Our results suggest that the 40-to-57 Ω-loop, which encompasses both naturally occurring cytochrome c mutations (G41S [1] and Y48H [2]), contributes to determining both the affinity of the cytochrome c interaction and the species specificity of the interaction. Three of the nine residue differences between human and mouse cytochromes c are located on this loop: P44A, Y46F and A50D (Fig 4A), and these residues also vary in Xenopus cytochrome c (E44, F46 and D50).…”

Section: Resultsmentioning

confidence: 99%

“…Thrombocytopenia Cargeeg (THC4; OMIM 612004) is one of two autosomal dominant thrombocytopenias associated with the only known mutations of the human cytochrome c gene ( CYCS ) [1,2]. Cytochrome c is an essential electron carrier in the mitochondrial respiratory chain and is also a critical mediator of the intrinsic apoptosis pathway.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Interspecies Variation in the Functional Consequences of Mutation of Cytochrome c

et al. 2015

View full text Add to dashboard Cite

The naturally occurring human cytochrome c variant (G41S) is associated with a mild autosomal dominant thrombocytopenia (Thrombocytopenia Cargeeg) caused by dysregulation of platelet production. The molecular basis of the platelet production defect is unknown. Despite high conservation of cytochrome c between human and mouse (91.4% identity), introducing the G41S mutation into mouse cytochrome c in a knockin mouse (Cycs G41S/G41S) did not recapitulate the low platelet phenotype of Thrombocytopenia Cargeeg. While investigating the cause of this disparity we found a lack of conservation of the functional impact of cytochrome c mutations on caspase activation across species. Mutation of cytochrome c at residue 41 has distinct effects on the ability of cytochrome c to activate caspases depending on the species of both the cytochrome c and its binding partner Apaf-1. In contrast to our previous results showing the G41S mutation increases the ability of human cytochrome c to activate caspases, here we find this activity is decreased in mouse G41S cytochrome c. Additionally unlike wildtype human cytochrome c, G41S cytochrome c is unable to activate caspases in Xenopus embryo extracts. Taken together these results demonstrate a previously unreported species-specific component to the interaction of cytochrome c with Apaf-1. This suggests that the electrostatic interaction between cytochrome c and Apaf-1 is not the sole determinant of binding, with additional factors controlling binding specificity and affinity. These results have important implications for studies of the effects of cytochrome c mutations on the intrinsic apoptosis pathway.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Interspecies Variation in the Functional Consequences of Mutation of Cytochrome c

et al. 2015

View full text Add to dashboard Cite

show abstract

“…There is no description of Cyt c deficiencies per se as mitochondrial diseases, perhaps because they are incompatible with life. To date, only two mutations in the CYC S gene have been described in patients suffering from a rare disease named thrombocytopenia 4 (De Rocco, 2014; Morison, 2008). …”

Section: Mouse Models Of Defect Of the Oxphos Electron Carriersmentioning

confidence: 99%

Mitochondrial Diseases Part I: Mouse models of OXPHOS deficiencies caused by defects in respiratory complex subunits or assembly factors

et al. 2015

View full text Add to dashboard Cite

Mitochondrial disorders are the most common inborn errors of metabolism affecting the oxidative phosphorylation system (OXPHOS). Because the poor knowledge of the pathogenic mechanisms, a cure for these disorders is still unavailable and all the treatments currently in use are supportive more than curative. Therefore, in the past decade a great variety of mouse models have been developed to assess the in vivo function of several mitochondrial proteins involved in human diseases. Due to the genetic and physiological similarity to humans, mice represent reliable models to study the pathogenic mechanisms of mitochondrial disorders and are precious to test new therapeutic approaches. Here we summarize the features of several mouse models of mitochondrial diseases directly related to defects in subunits of the OXPHOS complexes or in assembly factors. We discuss how these models recapitulate many human conditions and how they have contributed to the understanding of mitochondrial function in health and disease.

show abstract

Platelets and Their Disorders

Catani

Gasperi

Savini

et al. 2015

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

Platelets play a key role in haemostasis, inflammation and cancer biology. They show specific structural elements, including invaginations of the plasma membrane, a network of residual smooth endoplasmic reticulum, a highly specialized cytoskeleton maintaining the discoid structure of platelets and several kinds of organelles. Stimulation occurs by adhesion of platelets to sub‐endothelial matrix proteins, through the action of specific adhesion‐signalling receptors; soluble agonists (including ADP, thrombin, thromboxane A2) act as amplifiers of activation. A series of reactions (collectively forming the ‘outside‐in signalling’) triggers platelet spreading, granule secretion, aggregation and clot retraction. Defects in these complex signalling networks determine inherited or acquired platelet disorders, mainly characterized by altered haemostasis. Nowadays, genomic and post‐genomic techniques allow better identification and classification of platelet‐related diseases. Key Concepts Platelets are anucleated cells playing a crucial role in haemostasis and thrombosis, as well as in innate immunity, angiogenesis and cancer promotion. Platelet activation is a complex signalling network encompassing the response to multiple agonists and acting via interactions among several molecules (including integrins, G‐protein‐coupled receptors, protein kinases and phospholipases). Ultrastructural studies and omics approaches are ideal ways to investigate platelet sub‐cellular compartments and signalling pathways, playing a fundamental role in the pathogenesis of several pathologies. The recent identification of specific sub‐network defects in inherited platelet disorders will lead to understanding of the correlation between signal transduction pathways and cell functions. The identification of specific sub‐network defects in inherited platelet disorders will allow better classification of platelet‐related diseases.

show abstract

Mutations of cytochrome c identified in patients with thrombocytopenia THC4 affect both apoptosis and cellular bioenergetics

Cited by 72 publications

References 16 publications

Interspecies Variation in the Functional Consequences of Mutation of Cytochrome c

Interspecies Variation in the Functional Consequences of Mutation of Cytochrome c

Mitochondrial Diseases Part I: Mouse models of OXPHOS deficiencies caused by defects in respiratory complex subunits or assembly factors

Platelets and Their Disorders

Contact Info

Product

Resources

About