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Review
. 2023 Jan;34(1):21-33.
doi: 10.1016/j.tem.2022.11.001. Epub 2022 Nov 23.

Mitochondrial copper in human genetic disorders

Natalie M Garza  1 , Abhinav B Swaminathan  1 , Krishna P Maremanda  1 , Mohammad Zulkifli  1 , Vishal M Gohil  2
Affiliations
Review

Mitochondrial copper in human genetic disorders

Natalie M Garza et al. Trends Endocrinol Metab. 2023 Jan.

"V体育2025版" Abstract

Copper is an essential micronutrient that serves as a cofactor for enzymes involved in diverse physiological processes, including mitochondrial energy generation. Copper enters cells through a dedicated copper transporter and is distributed to intracellular cuproenzymes by copper chaperones. Mitochondria are critical copper-utilizing organelles that harbor an essential cuproenzyme cytochrome c oxidase, which powers energy production. Mutations in copper transporters and chaperones that perturb mitochondrial copper homeostasis result in fatal genetic disorders VSports手机版. Recent studies have uncovered the therapeutic potential of elesclomol, a copper ionophore, for the treatment of copper deficiency disorders such as Menkes disease. Here we review the role of copper in mitochondrial energy metabolism in the context of human diseases and highlight the recent developments in copper therapeutics. .

Keywords: Menkes disease; Wilson disease; copper; elesclomol; mitochondria; mitochondrial disease V体育安卓版. .

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Conflict of interest statement

Declaration of interests The authors’ university (Texas A&M) has entered into a licensing agreement with Engrail Therapeutics for the development of elesclomol:copper as a therapeutic agent for the disorders of copper metabolism VSports最新版本. Engrail therapeutics also sponsors certain aspects of elesclomol research in the author’s laboratory.

Figures

Figure 1.
Figure 1.
Copper trafficking in a polarized mammalian cell. Extracellular Cu2+ is reduced to Cu1+ by plasma membrane-localized reductases that allows its import via the high-affinity plasma membrane copper transporter CTR1. Extracellular Cu2+ could also be imported by a non-specific divalent metal transporter DMT1. Once in the cytosol, copper is immediately bound to either a non-proteinaceous ligand (GSH or CuL) or a metallochaperone for subsequent trafficking to various organelles. CuL is proposed to transport copper to mitochondria, where it is stored within the mitochondrial matrix and acts as a feedstock for the metallation of mitochondrial cuproenzymes. In the cytosol, CCS, a metallochaperone, binds and transfers copper to Cu/Zn SOD1. Copper is delivered to the Golgi lumen, via the combined action of cytosolic metallochaperone ATOX1 and the Golgi membrane localized copper pumps ATP7A and ATP7B. Recently, histones H3–H4 tetramer have been shown to act as copper reductases that increase the bioavailable copper pool by catalyzing the reduction of Cu2+ to Cu1+. Excess copper is either bound to metallothionein (MT) or pumped out of the cell via the action of ATP7A/B, which translocates to the plasma membrane via vesicular trafficking. The figure was created with Biorender.com.
Figure 2.
Figure 2.
Copper trafficking within mammalian mitochondria. Copper bound to a ligand (CuL) likely enters mitochondria via OMM localized porin and is then transported into the matrix by the IMM localized transporters SLC25A3 and MFRN1. The function of copper within the matrix is not known but this copper is transported back across the IMM by an unknown transporter. Once in the IMS, copper binds metallochaperones CCS and COX17, for its delivery to SOD1 and CcO, respectively. COX17 transfers copper to metallochaperones, COX11 and SCO1, which in turn inserts it into CcO subunits COX1 and COX2, respectively. COX11, COX19, and COA4 are components of the copper delivery pathway to the CuB site within the COX1 subunit. SCO1, SCO2, and COA6 are components of the copper delivery pathway to the CuA site within the COX2 subunit. The IMS-localized proteins COX23, CMC2, and COA5 are essential for CcO assembly but their involvement in the copper delivery pathway remains unknown. Abbreviations: OMM, outer mitochondrial membrane; IMS, intermembrane space; IMM, inner mitochondrial membrane. The figure was created with Biorender.com.
Figure 3.
Figure 3.
Cuproenzymes and their role in human physiology and pathology. The formal and abbreviated names of cuproenzymes as well as their enzymatic and physiological role(s) are listed. Typical clinical presentations of mitochondrial disorders, Menkes disease, and Wilson disease are depicted below, and causative enzyme(s) are indicated. Downward-facing arrows indicate reduced enzymatic activity. The figure was created with Biorender.com.
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