Impaired copper and iron metabolism in blood cells and muscles of patients affected by copper deficiency myeloneuropathy.
OBJECTIVE
Severe copper deficiency leads in humans to a treatable multisystem disease characterized by anaemia and degeneration of spinal cord and nerves, but its mechanisms have not been investigated. We tested whether copper deficit leads to alterations in fundamental copper-dependent proteins and in iron metabolism in blood and muscles of patients affected by copper deficiency myeloneuropathy, and if these metabolic abnormalities are associated with compensatory mechanisms for copper maintenance.


METHODS
We evaluated the expression of critical copper enzymes, of iron-related proteins, and copper chaperones and transporters in blood and muscles from five copper-deficient patients presenting with subacute sensory ataxia, muscle paralysis, liver steatosis and variable anaemia. Severe copper deficiency was caused by chronic zinc intoxication in all of the patients, with an additional history of gastrectomy in two cases.


RESULTS
The antioxidant enzyme SOD1 and subunit 2 of cytochrome c oxidase were significantly decreased in blood cells and in muscles of copper-deficient patients compared with controls. In muscle, the iron storage protein ferritin was dramatically reduced despite normal serum ferritin, and the expression of the haem-proteins cytochrome c and myoglobin was impaired. Muscle expression of the copper transporter CTR1 and of the copper chaperone CCS, was strikingly increased, while antioxidant protein 1 was diminished.


CONCLUSIONS
copper-dependent enzymes with critical functions in antioxidant defences, in mitochondrial energy production, and in iron metabolism are affected in blood and muscles of patients with profound copper deficiency leading to myeloneuropathy. Homeostatic mechanisms are strongly activated to increase intracellular copper retention.
Neuromuscular Laboratory, Department of Neurosciences, University of Padova, Padova, Italy.
Marco
M
Spinazzi
Angelo
A
Sghirlanzoni
Leonardo
L
Salviati
Corrado
C
Angelini
D000328:Adult; D000368:Aged; D001773:Blood Cells / Q000378:metabolism*; D003300:Copper / Q000172:deficiency* / Q000378:metabolism*; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D005293:Ferritins / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D013118:Spinal Cord Diseases / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D015032:Zinc / Q000633:toxicity
C000606290:SOD1 protein, human; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D003300:Copper; D005293:Ferritins; D007501:Iron; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D003576:Electron Transport Complex IV; D015032:Zinc
ataxia; copper deficiency; iron; myeloneuropathy; spinal cord disease; zinc