University of Oulu

Nair, R., Koivisto, H., Jokivarsi, K., Miinalainen, I., Autio, K., Manninen, A., Poutiainen, P., Tanila, H., Hiltunen, J., Kastaniotis, A. (2018) Impaired Mitochondrial Fatty Acid Synthesis Leads to Neurodegeneration in Mice. Journal of Neuroscience, 38 (45), 9781-9800.

Impaired mitochondrial fatty acid synthesis leads to neurodegeneration in mice

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Author: Nair, Remya R.1; Koivisto, Henna2; Jokivarsi, Kimmo2;
Organizations: 1Faculty of Biochemistry and Molecular Medicine
2A.I. Virtanen Institute, University of Eastern Finland, FI-70211 Kuopio, Finland
3Electron Microscopy Core Facility
4Virus Core Facility, Biocenter Oulu, University of Oulu, FI-90014 Oulu, Finland
5Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, FI-70029 Kuopio, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 12.9 MB)
Persistent link:
Language: English
Published: Society for Neuroscience, 2018
Publish Date: 2019-05-07


There has been a growing interest toward mitochondrial fatty acid synthesis (mtFAS) since the recent discovery of a neurodegenerative human disorder termed MEPAN (mitochondrial enoyl reductase protein associated neurodegeneration), which is caused by mutations in the mitochondrial enoyl-CoA/ACP (acyl carrier protein) reductase (MECR) carrying out the last step of mtFAS. We show here that MECR protein is highly expressed in mouse Purkinje cells (PCs). To elucidate mtFAS function in neural tissue, here, we generated a mouse line with a PC-specific knock-out (KO) of Mecr, leading to inactivation of mtFAS confined to this cell type. Both sexes were studied. The mitochondria in KO PCs displayed abnormal morphology, loss of protein lipoylation, and reduced respiratory chain enzymatic activities by the time these mice were 6 months of age, followed by nearly complete loss of PCs by 9 months of age. These animals exhibited balancing difficulties ∼7 months of age and ataxic symptoms were evident from 8–9 months of age on. Our data show that impairment of mtFAS results in functional and ultrastructural changes in mitochondria followed by death of PCs, mimicking aspects of the clinical phenotype. This KO mouse represents a new model for impaired mitochondrial lipid metabolism and cerebellar ataxia with a distinct and well trackable cellular phenotype. This mouse model will allow the future investigation of the feasibility of metabolite supplementation approaches toward the prevention of neurodegeneration due to dysfunctional mtFAS.

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Series: The Journal of neuroscience
ISSN: 0270-6474
ISSN-E: 1529-2401
ISSN-L: 0270-6474
Volume: 38
Issue: 45
Pages: 9781 - 9800
DOI: 10.1523/JNEUROSCI.3514-17.2018
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Funding: This work was supported by the Academy of Finland, the Sigrid Jusélius Foundation, the Finnish Cultural Foundation, the European Regional Development Fund project A71429, and Biocenter Finland.
Copyright information: © 2018 the Authors.