The mitochondrial metallochaperone SCO1 maintains CTR1 at the plasma membrane to preserve copper homeostasis in the murine heart

Zakery N Baker; Kimberly Jett; Aren Boulet; Amzad Hossain; Paul A Cobine; Byung-Eun Kim; Amr M El Zawily; Ling Lee; Glen F Tibbits; Michael J Petris; Scot C Leary

doi:10.1093/hmg/ddx344

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The mitochondrial metallochaperone SCO1 maintains CTR1 at the plasma membrane to preserve copper homeostasis in the murine heart

Journal article

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The mitochondrial metallochaperone SCO1 maintains CTR1 at the plasma membrane to preserve copper homeostasis in the murine heart

Zakery N Baker, Kimberly Jett, Aren Boulet, Amzad Hossain, Paul A Cobine, Byung-Eun Kim, Amr M El Zawily, Ling Lee, Glen F Tibbits, Michael J Petris, …

Human molecular genetics, Vol.26(23), pp.4617-4628

12/01/2017

DOI: 10.1093/hmg/ddx344

PMCID: PMC5886179

PMID: 28973536

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Abstract

SCO1 is a ubiquitously expressed, mitochondrial protein with essential roles in cytochrome c oxidase (COX) assembly and the regulation of copper homeostasis. SCO1 patients present with severe forms of early onset disease, and ultimately succumb from liver, heart or brain failure. However, the inherent susceptibility of these tissues to SCO1 mutations and the clinical heterogeneity observed across SCO1 pedigrees remain poorly understood phenomena. To further address this issue, we generated Sco1hrt/hrt and Sco1stm/stm mice in which Sco1 was specifically deleted in heart and striated muscle, respectively. Lethality was observed in both models due to a combined COX and copper deficiency that resulted in a dilated cardiomyopathy. Left ventricular dilation and loss of heart function was preceded by a temporal decrease in COX activity and copper levels in the longer-lived Sco1stm/stm mice. Interestingly, the reduction in copper content of Sco1stm/stm cardiomyocytes was due to the mislocalisation of CTR1, the high affinity transporter that imports copper into the cell. CTR1 was similarly mislocalized to the cytosol in the heart of knockin mice carrying a homozygous G115S substitution in Sco1, which in humans causes a hypertrophic cardiomyopathy. Our current findings in the heart are in marked contrast to our prior observations in the liver, where Sco1 deletion results in a near complete absence of CTR1 protein. These data collectively argue that mutations perturbing SCO1 function have tissue-specific consequences for the machinery that ultimately governs copper homeostasis, and further establish the importance of aberrant mitochondrial signaling to the etiology of copper handling disorders.

Animals

Cardiomyopathy, Hypertrophic - genetics

Cardiomyopathy, Hypertrophic - metabolism

Cation Transport Proteins - metabolism

Cell Membrane - metabolism

Copper - deficiency

Copper - metabolism

Copper Transporter 1

Disease Models, Animal

Electron Transport Complex IV - genetics

Electron Transport Complex IV - metabolism

Homeostasis

Ion Transport

Metallochaperones - genetics

Metallochaperones - metabolism

Mice

Mice, Transgenic

Mitochondria, Heart - metabolism

Mitochondrial Proteins - genetics

Mitochondrial Proteins - metabolism

Myocardium - metabolism

Myocytes, Cardiac - metabolism

Oxidation-Reduction

Signal Transduction

Details

Title: Subtitle: The mitochondrial metallochaperone SCO1 maintains CTR1 at the plasma membrane to preserve copper homeostasis in the murine heart
Creators: Zakery N Baker - Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
Kimberly Jett - Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
Aren Boulet - Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
Amzad Hossain - Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
Paul A Cobine - Department of Biological Sciences, Auburn University, Auburn, AL 36849, USA
Byung-Eun Kim - Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA
Amr M El Zawily - Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
Ling Lee - Department of Cardiovascular Sciences, BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada
Glen F Tibbits - Department of Cardiovascular Sciences, BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada
Michael J Petris - Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA
Scot C Leary - Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.26(23), pp.4617-4628
DOI: 10.1093/hmg/ddx344
PMID: 28973536
PMCID: PMC5886179
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Grant note: CIHR
Language: English
Date published: 12/01/2017
Academic Unit: Biology
Record Identifier: 9984217414802771

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