Mitochondrial Membrane Potential Is Reduced in Copper-Deficient C&lt;SUB&gt;2&lt;/SUB&gt;C&lt;SUB&gt;12&lt;/SUB&gt; Cells in the Absence of Apoptosis

Chen, Xiulian; Medeiros, Denis M.; Jennings, Dianne

doi:10.1385/bter:106:1:051

Cited by 15 publications

(7 citation statements)

References 25 publications

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“…Other investigators also demonstrated a beneficial effect of copper supplementation on streptozotocin-diabetic mice preventing ␤-cell death and diabetes development (43). Copper deficiency has been shown to reduce COX activity in cardiac mitochondria of nondiabetic rats, associating copper insufficiency with disruption of mitochondrial architecture (8,28,32,33,52), impaired mitochondrial oxidative phosphorylation, and reduced mitochondrial respiration (2,4,19). The finding that mitochondrial dysfunction is a factor in the development of diabetes has been assigned higher importance in the last decade, since mitochondrial DNA mutations in humans and ␤-cell-specific deletions of mitochondrial genes in animal models have been shown to cause diabetes (35,42,44).…”

Section: Discussionmentioning

confidence: 98%

Dietary copper supplementation restores β-cell function of Cohen diabetic rats: a link between mitochondrial function and glucose-stimulated insulin secretion

Weksler-Zangen

Jörns

Tarsi-Chen

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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β-Cell mitochondrial dysfunction as well as proinflammatory cytokines have been suggested to contribute to reduced glucose-stimulated insulin secretion (GSIS) in type 2 diabetes. We recently demonstrated that Cohen diabetic sensitive (CDs) rats fed a high-sucrose, low-copper diet (HSD) developed hyperglycemia and reduced GSIS in association with peri-islet infiltration of fat and interleukin (IL)-1β-expressing macrophages, whereas CD resistant (CDr) rats remained normoglycemic on HSD. We examined: 1) the correlation between copper concentration in the HSD and progression, prevention, and reversion of hyperglycemia in CDs rats, 2) the relationship between activity of the copper-dependent, respiratory-chain enzyme cytochrome c oxidase (COX), infiltration of fat, IL-1β-expressing macrophages, and defective GSIS in hyperglycemic CDs rats. CDs and CDr rats were fed HSD or copper-supplemented HSD before and during hyperglycemia development. Blood glucose and insulin concentrations were measured during glucose tolerance tests. Macrophage infiltration and IL-1β expression were evaluated in pancreatic sections by electron-microscopy and immunostaining. COX activity was measured in pancreatic sections and isolated islets. In CDs rats fed HSD, GSIS and islet COX activity decreased, while blood glucose and infiltration of fat and IL-1β-expressing macrophages increased with time on HSD (P < 0.01 vs. CDr-HSD rats, all parameters, respectively). CDs rats maintained on copper-supplemented HSD did not develop hyperglycemia, and in hyperglycemic CDs rats, copper supplementation restored GSIS and COX activity, reversed hyperglycemia and infiltration of fat and IL-1β-expressing macrophages (P < 0.01 vs. hyperglycemic CDs-HSD rats, all parameters, respectively). We provide novel evidence for a critical role of low dietary copper in diminished GSIS of susceptible CDs rats involving the combined consequence of reduced islet COX activity and pancreatic low-grade inflammation.

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Section: Discussionmentioning

confidence: 98%

Dietary copper supplementation restores β-cell function of Cohen diabetic rats: a link between mitochondrial function and glucose-stimulated insulin secretion

Weksler-Zangen

Jörns

Tarsi-Chen

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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“…Copper deprivation is known to reduce CIV activity (Dallman and Goodman, ; Medeiros and Wildman, ; Chen et al, 2002, ; Medeiros and Jennings, ), increase cellular ROS levels (Rossi et al, ; Arciello et al, ), and induce the formation of giant mitochondria (Dallman and Goodman, ; Goodman et al, ; Wakabayashi et al, ; Wakabayashi, ). Given this background, the aim of the current study was to understand the adaptive responses of mitochondria to mild copper deprivation in terms of OXPHOS remodeling, ETC function, and mitochondrial dynamics in vivo.…”

Section: Discussionmentioning

confidence: 99%

Adaptive Responses of Mitochondria to Mild Copper Deprivation Involve Changes in Morphology, OXPHOS Remodeling and Bioenergetics

Ruíz

Jensen

Bustos

et al. 2014

Journal Cellular Physiology

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Copper is an essential cofactor of complex IV of the electron transfer chain, and it is directly involved in the generation of mitochondrial membrane potential. Its deficiency induces the formation of ROS, large mitochondria and anemia. Thus, there is a connection between copper metabolism and bioenergetics, mitochondrial dynamics and erythropoiesis. Copper depletion might end in cellular apoptosis or necrosis. However, before entering into those irreversible processes, mitochondria may execute a series of adaptive responses. Mitochondrial adaptive responses (MAR) may involve multiple and diverse mechanisms for preserving cell life, such as mitochondrial dynamics, OXPHOS remodeling and bioenergetics output. In this study, a mild copper deficiency was produced in an animal model through intraperitoneal injections of bathocuproine disulfonate in order to study the MAR. Under these conditions, a new type of mitochondrial morphology was discovered in the liver. Termed the "butternut squash" mitochondria, it coexisted with normal and swollen mitochondria. Western blot analyses of mitochondrial dynamics proteins showed an up-regulation of MFN-2 and OPA1 fusion proteins. Furthermore, isolated liver mitochondria displayed OXPHOS remodeling through a decrease in supercomplex activity with a concomitant increase at an individual level of complexes I and IV, higher respiratory rates at complex I and II levels, higher oligomycin-insensitive respiration, and lower respiratory control ratio values when compared to the control group. As expected, total ATP and ATP/ADP values were not significantly different, since animal's health was not compromised. As a whole, these results describe a compensatory and adaptive response of metabolism and bioenergetics under copper deprivation.

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“…Indeed, complex IV serves as a metal sensor in the regulation of respiratory rates ( Desler et al, 2012 ). Supporting this mechanism, copper deficiency reduces the expression and activity of complex IV ( Dallman and Goodman 1970 ; Chen et al, 2002 ; Medeiros and Jennings 2002 ; Chen et al, 2005 ; Zeng et al, 2007 ; Ruiz et al, 2014 ), but not the other respiratory complexes ( Zeng et al, 2007 ; Bustos et al, 2013 ). Regarding copper overload, the current results showed an increase in complex IV protein expression ( Ruiz et al, 2016 ).…”

Section: Getting Copper Into Mitochondriamentioning

confidence: 99%

Role of Copper on Mitochondrial Function and Metabolism

Ruíz

Libedinsky

Elorza

2021

Front. Mol. Biosci.

297

174

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Copper is essential for life processes like energy metabolism, reactive oxygen species detoxification, iron uptake, and signaling in eukaryotic organisms. Mitochondria gather copper for the assembly of cuproenzymes such as the respiratory complex IV, cytochrome c oxidase, and the antioxidant enzyme superoxide dismutase 1. In this regard, copper plays a role in mitochondrial function and signaling involving bioenergetics, dynamics, and mitophagy, which affect cell fate by means of metabolic reprogramming. In mammals, copper homeostasis is tightly regulated by the liver. However, cellular copper levels are tissue specific. Copper imbalances, either overload or deficiency, have been associated with many diseases, including anemia, neutropenia, and thrombocytopenia, as well as tumor development and cancer aggressivity. Consistently, new pharmacological developments have been addressed to reduce or exacerbate copper levels as potential cancer therapies. This review goes over the copper source, distribution, cellular uptake, and its role in mitochondrial function, metabolic reprograming, and cancer biology, linking copper metabolism with the field of regenerative medicine and cancer.

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Mitochondrial Membrane Potential Is Reduced in Copper-Deficient C<SUB>2</SUB>C<SUB>12</SUB> Cells in the Absence of Apoptosis

Cited by 15 publications

References 25 publications

Dietary copper supplementation restores β-cell function of Cohen diabetic rats: a link between mitochondrial function and glucose-stimulated insulin secretion

Dietary copper supplementation restores β-cell function of Cohen diabetic rats: a link between mitochondrial function and glucose-stimulated insulin secretion

Adaptive Responses of Mitochondria to Mild Copper Deprivation Involve Changes in Morphology, OXPHOS Remodeling and Bioenergetics

Role of Copper on Mitochondrial Function and Metabolism

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