Many observers have noted that the morphological changes that occur in chronic kidney disease(CKD) patients resemble those seen in the geriatric population, with strikingly similar morbidity and mortality profiles and...Many observers have noted that the morphological changes that occur in chronic kidney disease(CKD) patients resemble those seen in the geriatric population, with strikingly similar morbidity and mortality profiles and rates of frailty in the two groups, and shared characteristics at a pathophysiological level especially in respect to the changes seen in their vascular andimmune systems. However, whilst much has been documented about the shared physical characteristics of aging and uremia, the molecular and cellular similarities between the two have received less attention. In order to bridge this perceived gap we have reviewed published research concerning the common molecular processes seen in aging subjects and CKD patients, with specific attention to altered proteostasis, mitochondrial dysfunction, post-translational protein modification, and senescence and telomere attrition. We have also sought to illustrate how the cell death and survival pathways apoptosis, necroptosis and autophagy are closely interrelated, and how an understanding of these overlapping pathways is helpful in order to appreciate the shared molecular basis behind the pathophysiology of aging and uremia. This analysis revealed many common molecular characteristics and showed similar patterns of cellular dysfunction. We conclude that the accelerated aging seen in patients with CKD is underpinned at the molecular level, and that a greater understanding of these molecular processes might eventually lead to new much needed therapeutic strategies of benefit to patients with renal disease.展开更多
Cytochromes c covalently bind their heme prosthetic groups through thioether bonds between the vinyl groups of the heme and the thiols of a CXXCH motif within the protein.In Gramnegative bacteria,this process is catal...Cytochromes c covalently bind their heme prosthetic groups through thioether bonds between the vinyl groups of the heme and the thiols of a CXXCH motif within the protein.In Gramnegative bacteria,this process is catalyzed by the Ccm(cytochrome c maturation)proteins,also called System I.The Ccm proteins are found in the bacterial inner membrane,but some(CcmE,CcmG,CcmH,and CcmI)also have soluble functional domains on the periplasmic face of the membrane.Elucidation of the mechanisms involved in the transport and relay of heme and the apo-cytochrome from the bacterial cytosol into the periplasm,and their subsequent reaction,has proved challenging due to the fact that most of the proteins involved are membrane-associated,but recent progress in understanding some key components has thrown up some surprises.In this Review,we discuss advances in our understanding of this process arising from a substrate’s point of view and from recent structural information about individual components.展开更多
文摘Many observers have noted that the morphological changes that occur in chronic kidney disease(CKD) patients resemble those seen in the geriatric population, with strikingly similar morbidity and mortality profiles and rates of frailty in the two groups, and shared characteristics at a pathophysiological level especially in respect to the changes seen in their vascular andimmune systems. However, whilst much has been documented about the shared physical characteristics of aging and uremia, the molecular and cellular similarities between the two have received less attention. In order to bridge this perceived gap we have reviewed published research concerning the common molecular processes seen in aging subjects and CKD patients, with specific attention to altered proteostasis, mitochondrial dysfunction, post-translational protein modification, and senescence and telomere attrition. We have also sought to illustrate how the cell death and survival pathways apoptosis, necroptosis and autophagy are closely interrelated, and how an understanding of these overlapping pathways is helpful in order to appreciate the shared molecular basis behind the pathophysiology of aging and uremia. This analysis revealed many common molecular characteristics and showed similar patterns of cellular dysfunction. We conclude that the accelerated aging seen in patients with CKD is underpinned at the molecular level, and that a greater understanding of these molecular processes might eventually lead to new much needed therapeutic strategies of benefit to patients with renal disease.
基金supported in PDB's lab by the BBSRC and an EPSRC studentship to EBS.EBS is currently supported by a Chinese Academy of Sciences Fellowship for Young International Scientists(No.2010Y2SB01)a grant from the National Natural Science Foundation of China(Grant No.31150110150).
文摘Cytochromes c covalently bind their heme prosthetic groups through thioether bonds between the vinyl groups of the heme and the thiols of a CXXCH motif within the protein.In Gramnegative bacteria,this process is catalyzed by the Ccm(cytochrome c maturation)proteins,also called System I.The Ccm proteins are found in the bacterial inner membrane,but some(CcmE,CcmG,CcmH,and CcmI)also have soluble functional domains on the periplasmic face of the membrane.Elucidation of the mechanisms involved in the transport and relay of heme and the apo-cytochrome from the bacterial cytosol into the periplasm,and their subsequent reaction,has proved challenging due to the fact that most of the proteins involved are membrane-associated,but recent progress in understanding some key components has thrown up some surprises.In this Review,we discuss advances in our understanding of this process arising from a substrate’s point of view and from recent structural information about individual components.
