Organelles in focus
Mitochondrial copper homeostasis and its derailment in Wilson disease

https://doi.org/10.1016/j.biocel.2018.07.001Get rights and content
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Highlights

  • Mitochondria harbor the copper–dependent enzymes cytochrome c oxidase and superoxide dismutase 1, and thus require an adequate copper supply.

  • Copper chaperones that hand over copper by protein-protein interactions enable the activity of copper-dependent enzymes in mitochondria.

  • A large part of molecular players that supply the metal to the mitochondrial copper–dependent enzymes have been identified.

  • Uncertainties exist with respect to the molecular mechanisms for mitochondrial metal uptake, storage and release.

  • Copper overload causes structural, biochemical and biophysical mitochondrial deficits in Wilson disease patients and related animal models.

  • Copper depletion restores mitochondrial structure and function and avoid liver failure in Wilson disease patients and related animal models.

Abstract

In mitochondria, copper is a Janus-faced trace element. While it is the essential cofactor of the mitochondrial cytochrome c oxidase, a surplus of copper can be highly detrimental to these organelles. On the one hand, mitochondria are strictly dependent on adequate copper supply for proper respiratory function, and the molecular mechanisms for metalation of the cytochrome c oxidase have been largely characterized. On the other hand, copper overload impairs mitochondria and uncertainties exist concerning the molecular mechanisms for mitochondrial metal uptake, storage and release. The latter issue is of fundamental importance in Wilson disease, a genetic disease characterized by dysfunctional copper excretion from the liver. Prime consequences of the progressive copper accumulation in hepatocytes are increasing mitochondrial biophysical and biochemical deficits. Focusing on this two-sided aspect of mitochondrial copper, we review mitochondrial copper homeostasis but also the impact of excessive mitochondrial copper in Wilson disease.

Abbreviations

ATP7B
ATPase copper transporting beta
CcO
cytochrome c oxidase
CCS
copper chaperone for superoxide dismutase
COX1
cytochrome c oxidase subunit 1
COX2
cytochrome c oxidase subunit 2
COX11
cytochrome c oxidase assembly protein 11
COX17
cytochrome c oxidase copper chaperone 17
COX19
cytochrome c oxidase assembly protein 19
COX23
cytochrome c oxidase assembly protein 23
CuL
copper ligand
D-PA
D-penicillamine
GI
gastrointestinal tract
GSH
glutathione
GSSG
glutathione disulfide
HEK293
human embryonic kidney 293 cell line
IMS
intermembrane space
KCu
Cu1+-binding dissociation constant
LEC
Long-Evans Cinnamon rat
LPP
crossbred from Long-Evans Cinnamon rat and Piebald Virol Glaxo rat
MFRN1
mitoferrin 1
MOM
mitochondrial outer membrane
ROS
reactive oxygen species
SCO1/2
synthesis of cytochrome c oxidase proteins 1/2
SLC25A3
solute carrier family 25 member 3
SOD1
superoxide dismutase 1
TGN
trans-Golgi network
WD
Wilson disease

Keywords

Mitochondria
Liver
Wilson disease
Copper

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