Modeling human Coenzyme A synthase mutation in yeast reveals altered mitochondrial function, lipid content and iron metabolism.

Camilla Berti,Department Of Life Sciences, University Of Parma, Parma, Italy ,Cristina Dallabona,Valeria Tiranti,Sabrina Dusi,Mirca Lazzaretti,Paola Goffrini,Elena Tosi

doi:10.15698/mic2015.04.196

Camilla Berti, Department Of Life Sciences, University Of Parma, Parma, Italy + Show 6 more

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https://doi.org/10.15698/mic2015.04.196

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Journal: Microbial cell (Graz, Austria)	Publication Date: Apr 6, 2015
Citations: 15	License type: cc-by

Affiliation: University of Parma

Abstract

Mutations in nuclear genes associated with defective coenzyme A biosynthesis have been identified as responsible for some forms of neurodegeneration with brain iron accumulation (NBIA), namely PKAN and CoPAN. PKAN are defined by mutations in PANK2, encoding the pantothenate kinase 2 enzyme, that account for about 50% of cases of NBIA, whereas mutations in CoA synthase COASY have been recently reported as the second inborn error of CoA synthesis leading to CoPAN. As reported previously, yeast cells expressing the pathogenic mutation exhibited a temperature-sensitive growth defect in the absence of pantothenate and a reduced CoA content. Additional characterization revealed decreased oxygen consumption, reduced activities of mitochondrial respiratory complexes, higher iron content, increased sensitivity to oxidative stress and reduced amount of lipid droplets, thus partially recapitulating the phenotypes found in patients and establishing yeast as a potential model to clarify the pathogenesis underlying PKAN and CoPAN diseases.

Highlights

In all living cells Coenzyme A (CoA) is the major carrier of acetyl and acyl groups playing a central role in basic cellular functions such as lipids metabolism, Krebs cycle and aminoacid biosynthesis
pantothenate kinase associated neurodegeneration (PKAN) are defined by mutations in PANK2, encoding the pantothenate kinase 2 enzyme, that account for about 50% of cases of neurodegeneration with brain iron accumulation (NBIA), whereas mutations in CoA synthase Coenzyme A synthase (COASY) have been recently reported as the second inborn error of CoA synthesis leading to COASY protein-associated neurodegeneration (CoPAN)
Whereas in mammals the last two steps are catalyzed by Coenzyme A synthase (COASY), a mitochondrial bifunctional enzyme possessing both 4’-phospho-pantetheine adenylyltransferase (PPAT) and dephospho-CoA kinase (DPCK) activities [1, 2], in other organisms, such as yeast, PPAT and DPCK activities reside in two different enzymes, Cab4 and Cab5, the products of the essential genes CAB4 and CAB5 [3] whose compartmentalization is not well understood

Summary

Introduction

In all living cells Coenzyme A (CoA) is the major carrier of acetyl and acyl groups playing a central role in basic cellular functions such as lipids metabolism, Krebs cycle and aminoacid biosynthesis. It has been reported that dysfunctions of CoA biosynthetic pathway may play a role in the pathogenesis of neurodegeneration with brain iron accumulation (NBIA), a wide spectrum of clinically and genetically heterogeneous diseases characterized by progressive neurodegeneration and high iron content in specific brain region [4, 5, 6]. This concept is supported by the fact that mutations in PANK2, encoding the first enzyme in the CoA synthesis, approximately account for 50% of NBIA cases, classified as PKAN (Pantothenate Kinase Associated Neurodegeneration) [7, 8]. COASY gene has been identified as a novel NBIA-associated gene and these NBIA cases have been termed CoPAN (COASY Protein-Associated Neurodegeneration)[9]

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