University of Oulu

Geoffray Monteuuis, Fumi Suomi, Juha M. Kerätär, Ali J. Masud, Alexander J. Kastaniotis A conserved mammalian mitochondrial isoform of acetyl-CoA carboxylase ACC1 provides the malonyl-CoA essential for mitochondrial biogenesis in tandem with ACSF3 Biochemical Journal Nov 2017, 474 (22) 3783-3797; DOI: 10.1042/BCJ20170416

A conserved mammalian mitochondrial isoform of acetyl-CoA carboxylase ACC1 provides the malonyl-CoA essential for mitochondrial biogenesis in tandem with ACSF3

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Author: Monteuuis, Geoffray1; Suomi, Fumi1; Kerätär, Juha M.1;
Organizations: 1Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu FI-90014, Finland
Format: article
Version: accepted version
Access: embargoed
Persistent link: http://urn.fi/urn:nbn:fi-fe2017112855099
Language: English
Published: Portland Press, 2017
Publish Date: 2018-11-06
Description:

Abstract

Mitochondrial fatty acid synthesis (mtFAS) is a highly conserved pathway essential for mitochondrial biogenesis. The mtFAS process is required for mitochondrial respiratory chain assembly and function, synthesis of the lipoic acid cofactor indispensable for the function of several mitochondrial enzyme complexes and essential for embryonic development in mice. Mutations in human mtFAS have been reported to lead to neurodegenerative disease. The source of malonyl-CoA for mtFAS in mammals has remained unclear. We report the identification of a conserved vertebrate mitochondrial isoform of ACC1 expressed from an ACACA transcript splicing variant. A specific knockdown (KD) of the corresponding transcript in mouse cells, or CRISPR/Cas9-mediated inactivation of the putative mitochondrial targeting sequence in human cells, leads to decreased lipoylation and mitochondrial fragmentation. Simultaneous KD of ACSF3, encoding a mitochondrial malonyl-CoA synthetase previously implicated in the mtFAS process, resulted in almost complete ablation of protein lipoylation, indicating that these enzymes have a redundant function in mtFAS. The discovery of a mitochondrial isoform of ACC1 required for lipoic acid synthesis has intriguing consequences for our understanding of mitochondrial disorders, metabolic regulation of mitochondrial biogenesis and cancer.

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Series: Biochemical journal
ISSN: 0264-6021
ISSN-E: 1470-8728
ISSN-L: 0264-6021
Volume: 22
Issue: 474
Pages: 3783 - 3797
DOI: 10.1042/BCJ20170416
OADOI: https://oadoi.org/10.1042/BCJ20170416
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
1184 Genetics, developmental biology, physiology
3111 Biomedicine
Subjects:
Funding: This work was supported by the Academy of Finland, the Sigrid Juselius Foundation, the Biocenter Oulu and AFM-Téléthon.
Academy of Finland Grant Number: 131369
Detailed Information: 131369 (Academy of Finland Funding decision)
Copyright information: © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society