Sending copper where it is needed most

doi:10.1126/science.abb6662

GSTDTAP > 气候变化

DOI	10.1126/science.abb6662
	Sending copper where it is needed most
	Svetlana Lutsenko
	2020-05-08
发表期刊	Science
出版年	2020
英文摘要	Copper (Cu) is an essential component of human physiology, and it is indispensable for normal brain development. Cells use Cu in many processes, including respiration, formation of myelin sheath, immune responses, wound healing, and synthesis of neurotransmitters ([ 1 ][1]). A sophisticated network of Cu-transporting proteins retrieves Cu from dietary sources, transfers Cu across biological membranes, and distributes it within cells and tissues ([ 2 ][2]). The key component of this network, Cu-transporting adenosine triphosphatase 1 (ATP7A), is inactivated in Menkes disease (MNKD). This causes Cu deficit in the brain, neurodegeneration, and early death. Cu supplementation is ineffective in treating MNKD patients because Cu cannot reach many cellular destinations, especially the brain, without functional transporters. On page 620 of this issue, Guthrie et al. ([ 3 ][3]) show that a small Cu-binding molecule, elesclomol, can overcome this problem, improving Cu delivery to the brain and alleviating mortality of ATP7A-deficient mice. Cu is a fascinating metal. Its malleability, attractive color, and conductivity make Cu a metal of choice for many applications. The role of Cu in human physiology is much less appreciated. This is largely because the daily dietary requirements for Cu are low (only 1 to 2 mg per day) and the genetic disorders of Cu homeostasis are relatively rare. The discovery in 1993 of genes associated with MNKD ( ATP7A ) and Wilson's disease ( ATP7B , which causes a buildup of Cu in the body) highlighted the role of Cu balance in human physiology and revealed the existence of proteins responsible for Cu transport and distribution ([ 4 ][4]–[ 7 ][5]). The list of Cu-handling proteins as well as disorders associated with Cu imbalance has been growing. MNKD and Wilson's disease illustrate negative consequences of either Cu deficiency or Cu overload, respectively, and the challenges associated with treatment of these disorders. MNKD and Wilson's disease are caused by inactivating mutations in similar Cu-transporting proteins, which have tissue-specific functions. ATP7A facilitates Cu export from the intestine into the blood for further utilization including Cu import to the brain, whereas ATP7B exports excess Cu from the liver for removal in bile. These functions are essential for human life. ATP7A also plays an equally important role within cells: It transports Cu from the cytosol into the lumen of specialized cellular compartments (trans-Golgi network, vesicles, and secretory granules), where Cu is used to activate various Cu-dependent enzymes (see the figure). Loss of ATP7A activity causes systemic Cu deficiency, poor temperature control, abnormal formation of connective tissues and vasculature, demyelination of neurons, seizures, developmental delay, and death at the age of 3 to 4 years. Inactivation of ATP7B is also debilitating: It leads to Cu overload in tissues, liver disease, and neurological and psychiatric abnormalities. In both cases, restoring proper distribution of Cu within cells and tissues remains a major challenge. MNKD is especially difficult to treat and, currently, there is no cure. Early diagnosis followed by prompt Cu supplementation with Cu-histidine complex may prolong patients' lives and improve motor skills and neurodevelopment ([ 8 ][6]). Cu-histidine is delivered intravenously and has to cross many biological barriers to reach Cu-dependent proteins within the central nervous system. In the absence of ATP7A, this process is inefficient, and Cu-histidine–treated MNKD patients die before reaching adulthood. Promising progress has been made toward gene therapy for MNKD ([ 9 ][7]), but safe gene transfer to neonatal brain remains a future goal. Furthermore, gene transfer is typically targeted to specific tissues, leaving others “uncorrected.” Small molecules are less tissue specific and may facilitate broad balancing of Cu throughout the body. Using mouse models of Cu deficiency, Guthrie et al. found that the small molecule elesclomol can carry Cu through various biological membranes and facilitate delivery to Cu-dependent enzymes, especially in mitochondria. ![Figure][8] Elesclomol facilitates membrane transfer of copper Copper (Cu)–transporting adenosine triphosphatase 1 (ATP7A) exports Cu from the gut into the bloodstream and facilitates Cu entry through the blood-brain barrier (BBB) into the brain parenchyma. Within cells, ATP7A transports Cu into the trans-Golgi network and vesicles. In Atp7a -deficient mice, elesclomol binds Cu (ES-Cu) and transfers Cu through biological membranes to mitochondria, activating cytochrome c oxidase (CCO). GRAPHIC: A. KITTERMAN/ SCIENCE Mitochondria ar e distinctly sensitive to Cu imbalance and their functions are often compromised in Cu-associated disorders ([ 10 ][9], [ 11 ][10]). In MNKD, an essential mitochondrial metabolic protein, cytochrome c oxidase (CCO), exhibits reduced activity. Mitochondrial dysfunction contributes to neurodegeneration in MNKD ([ 12 ][11]) and restoring CCO activity is necessary for successful treatment. Using a mouse model of MNKD, Guthrie et al. showed that treatment with elesclomol increased CCO activity, improved oxygen consumption by mitochondria, normalized brain structures, improved neurologic functions, and markedly decreased mortality. A slight improvement of poor pigmentation and curly whiskers (both reflections of Cu deficiency in cellular compartments outside mitochondria) suggests that elesclomol-Cu facilitates Cu distribution throughout the cell. Many important Cu-dependent enzymes are located within the cells' secretory pathway, and their activity is greatly diminished in MNKD patients and animal models of the disease. Even partial recovery of their activity is consequential, because it helps to restore production of neurotransmitters, vasculature formation, and other processes. The authors show that elesclomol acts as a Cu shuttle—in a complex with Cu—and it does not appear to have obvious toxic effects in mice. Guthrie et al. offer convincing evidence that it is possible for a small molecule to carry Cu through complex biological barriers and improve Cu metabolism in tissues. It is important to note that, over time, Cu delivered by elesclomol is metabolized and additional Cu-elesclomol delivery is needed to maintain Cu-dependent enzymes in the brain. The rate of Cu entry into the brain is relatively high at the early stages of brain development, but it drops substantially in adult animals. It remains unclear whether Cu supplied during early brain development is sufficient to sustain brain function in adult life. Further studies are also needed to determine whether, in addition to Cu transfer to mitochondria, more efficient Cu transport to the trans-Golgi network and other cellular destinations can be achieved. This could also be important for Wilson's disease. Cu-dependent enzymes that undergo functional maturation inside the trans-Golgi network and various granules critically contribute to brain regulatory and signaling functions and should not be overlooked in a search for therapeutic approaches for MNKD and other diseases of Cu imbalance. Elesclomol offers a starting point toward developing a vehicle for delivery of Cu where it is needed most. 1. [↵][12]1. I. F. Scheiber et al ., Prog. Neurobiol. 116, 33 (2014). [OpenUrl][13][CrossRef][14][PubMed][15] 2. [↵][16]1. S. Lutsenko , Metallomics 8, 840 (2016). [OpenUrl][17] 3. [↵][18]1. L. M. Guthrie et al ., Science 368, 620 (2020). [OpenUrl][19][Abstract/FREE Full Text][20] 4. [↵][21]1. J. F. Mercer et al ., Nat. Genet. 3, 20 (1993). [OpenUrl][22][CrossRef][23][PubMed][24][Web of Science][25] 5. 1. C. Vulpe et al ., Nat. Genet. 3, 7 (1993). [OpenUrl][26][CrossRef][27][PubMed][28][Web of Science][29] 6. 1. P. C. Bull et al ., Nat. Genet. 5, 327 (1993). [OpenUrl][30][CrossRef][31][PubMed][32][Web of Science][33] 7. [↵][34]1. R. E. Tanzi et al ., Nat. Genet. 5, 344 (1993). [OpenUrl][35][CrossRef][36][PubMed][37][Web of Science][38] 8. [↵][39]1. S. G. Kaler , J. Trace Elem. Med. Biol. 28, 427 (2014). [OpenUrl][40][CrossRef][41][PubMed][42] 9. [↵][43]1. M. R. Haddad et al ., Mol. Ther. Methods Clin. Dev. 10, 165 (2018). [OpenUrl][44][CrossRef][45][PubMed][46] 10. [↵][47]1. A. Członkowska et al ., Nat. Rev. Dis. Primers 4, 21 (2018). [OpenUrl][48] 11. [↵][49]1. N. Zakery et al ., Metallomics 9, 1501 (2017). [OpenUrl][50][CrossRef][51][PubMed][52] 12. [↵][53]1. S. Zlatic et al ., Neurobiol. Dis. 81, 154 (2015). [OpenUrl][54][CrossRef][55][PubMed][56] Acknowledgments: This work was supported by National Institutes of Health grant R01 GM101502 to S.L. 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领域	气候变化 ; 资源环境
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引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/249789
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Svetlana Lutsenko. Sending copper where it is needed most[J]. Science,2020.
APA	Svetlana Lutsenko.(2020).Sending copper where it is needed most.Science.
MLA	Svetlana Lutsenko."Sending copper where it is needed most".Science (2020).