Author
Sabine Borchard
Bio: Sabine Borchard is an academic researcher. The author has contributed to research in topics: Copper toxicity & Mitochondrion. The author has an hindex of 8, co-authored 12 publications receiving 300 citations.
Papers
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TL;DR: An update regarding the key roles of ROS-mitochondria cross talk in different fundamental physiological or pathological situations accompanying aging is provided, highlighting that mitochondrial ROS may be a decisive target in clinical practice.
Abstract: Aging has been linked to several degenerative processes that, through the accumulation of molecular and cellular damage, can progressively lead to cell dysfunction and organ failure. Human aging is linked with a higher risk for individuals to develop cancer, neurodegenerative, cardiovascular, and metabolic disorders. The understanding of the molecular basis of aging and associated diseases has been one major challenge of scientific research over the last decades. Mitochondria, the center of oxidative metabolism and principal site of reactive oxygen species (ROS) production, are crucial both in health and in pathogenesis of many diseases. Redox signaling is important for the modulation of cell functions and several studies indicate a dual role for ROS in cell physiology. In fact, high concentrations of ROS are pathogenic and can cause severe damage to cell and organelle membranes, DNA, and proteins. On the other hand, moderate amounts of ROS are essential for the maintenance of several biological processes, including gene expression. In this review, we provide an update regarding the key roles of ROS-mitochondria cross talk in different fundamental physiological or pathological situations accompanying aging and highlighting that mitochondrial ROS may be a decisive target in clinical practice.
174 citations
TL;DR: ATP7B-deficient hepatocytes, such as in those in patients with WD, activate autophagy in response to copper overload to prevent copper-induced apoptosis, and agents designed to activate this autophagic pathway might decrease copper toxicity in Patients with WD.
124 citations
TL;DR: This work presents an efficient method to isolate functionally active, intact mitochondria from cultured or primary cells and minute tissue samples in a rapid, highly reproducible manner.
52 citations
TL;DR: WD-mitochondria do not promote steatotic wild type and immune-compromised mice fed a Western diet, but demonstrate bioenergetic deficits and increased sensitivity to stress signals.
45 citations
TL;DR: A high-calorie diet severely aggravates hepatic mitochondrial and hepatocellular damage in Wilson disease rats, causing an earlier onset of the disease and enhanced disease progression.
Abstract: Background & Aims In Wilson disease, ATP7B mutations impair copper excretion into bile. Hepatic copper accumulation may induce mild to moderate chronic liver damage or even acute liver failure. Etiologic factors for this heterogeneous phenotype remain enigmatic. Liver steatosis is a frequent finding in Wilson disease patients, suggesting that impaired copper homeostasis is linked with liver steatosis. Hepatic mitochondrial function is affected negatively both by copper overload and steatosis. Therefore, we addressed the question of whether a steatosis-promoting high-calorie diet aggravates liver damage in Wilson disease via amplified mitochondrial damage. Methods Control Atp7b+/- and Wilson disease Atp7b-/- rats were fed either a high-calorie diet (HCD) or a normal diet. Copper chelation using the high-affinity peptide methanobactin was used in HCD-fed Atp7b-/- rats to test for therapeutic reversal of mitochondrial copper damage. Results In comparison with a normal diet, HCD feeding of Atp7b-/- rats resulted in a markedly earlier onset of clinically apparent hepatic injury. Strongly increased mitochondrial copper accumulation was observed in HCD-fed Atp7b-/- rats, correlating with severe liver injury. Mitochondria presented with massive structural damage, increased H2O2 emergence, and dysfunctional adenosine triphosphate production. Hepatocellular injury presumably was augmented as a result of oxidative stress. Reduction of mitochondrial copper by methanobactin significantly reduced mitochondrial impairment and ameliorated liver damage. Conclusions A high-calorie diet severely aggravates hepatic mitochondrial and hepatocellular damage in Wilson disease rats, causing an earlier onset of the disease and enhanced disease progression.
45 citations
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TL;DR: It is demonstrated that selenolate-based catalysis of the essential mammalian selenoprotein GPX4 is unexpectedly dispensable for normal embryogenesis and the survival of a specific type of interneurons emerges to exclusively depend on selenocysteine-containing GPX 4, thereby preventing fatal epileptic seizures.
759 citations
TL;DR: This paper showed that tumor cells without mitochondrial DNA (mtDNA) showed delayed tumor growth, and that tumor formation is associated with acquisition of mtDNA from host cells, leading to partial recovery of mitochondrial function in cells derived from primary tumors grown from cells without mtDNA and a shorter lag in tumor growth.
548 citations
University of Michigan1, Cornell University2, University of Pennsylvania3, University of Massachusetts Medical School4, Baylor College of Medicine5, University of Naples Federico II6, Spanish National Research Council7, Complutense University of Madrid8, New York University9, Boston Children's Hospital10, University of Rome Tor Vergata11, NewYork–Presbyterian Hospital12, University of Pittsburgh13, University of Paris14, French Institute of Health and Medical Research15, National University of Cuyo16, Albert Einstein College of Medicine17, University of New Mexico18, Goethe University Frankfurt19, Weizmann Institute of Science20, University of Turku21, Sapienza University of Rome22, Virginia Commonwealth University23, St. Jude Children's Research Hospital24, Discovery Institute25, University of Copenhagen26, University of Tromsø27, Eötvös Loránd University28, Merck & Co.29, University of Freiburg30, Babraham Institute31, University of Adelaide32, University of South Australia33, University of Oviedo34, University of Chicago35, University of Graz36, National Institutes of Health37, Queens College38, City University of New York39, University of Tokyo40, University of Zurich41, Austrian Academy of Sciences42, University of British Columbia43, University of California, San Francisco44, Russian Academy of Sciences45, University Medical Center Groningen46, University of Cambridge47, University of Glasgow48, Rutgers University49, University of Padua50, University of Bern51, Kazan Federal University52, University of Oxford53, Oslo University Hospital54, University of Oslo55, Foundation for Research & Technology – Hellas56, University of Crete57, Francis Crick Institute58, Osaka University59, Harvard University60, Chinese Academy of Sciences61, Icahn School of Medicine at Mount Sinai62, Shanghai Jiao Tong University63, Karolinska Institutet64
TL;DR: In this paper, preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.
Abstract: Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.
365 citations
06 Sep 2018
TL;DR: Wilson disease (WD) is a potentially treatable, inherited disorder of copper metabolism characterised by pathological copper accumulation as mentioned in this paper, which is caused by mutations in the ATP7B gene, which encodes a transmembrane copper-transporting ATPase, leading to copper overload in the liver, brain and other organs.
Abstract: Wilson disease (WD) is a potentially treatable, inherited disorder of copper metabolism characterised by pathological copper accumulation. WD is caused by mutations in the ATP7B gene, which encodes a transmembrane copper-transporting ATPase, leading to copper overload in the liver, brain and other organs. The clinical course of WD can vary in severity but progressive liver disease is a common feature. Patients can also present with neurological disorders and psychiatric symptoms. WD is diagnosed based on diagnostic algorithms incorporating clinical symptoms and signs, measures of copper metabolism and DNA analysis. Available treatments include chelators and zinc salts, which reverse copper overload by different mechanisms. Additionally, liver transplantation is indicated in selected cases. New agents, such as tetrathiomolybdate salts, are currently being investigated in clinical trials and genetic therapies are being tested in animal models. With early treatment, the prognosis of disease is good; however, an important issue is diagnosing patients before the onset of serious symptoms. Advances in screening for WD may therefore bring earlier diagnosis and improvements for patients with this disorder.
330 citations