Elovl2-Ablation Leads to Mitochondrial Membrane Fatty Acid Remodeling and Reduced Efficiency in Mouse Liver Mitochondria

Alexia Gómez Rodríguez,Gustavo Barja,Alba Naudi,Anastasia V Kalinovich,Anders Jacobsson,Reinald Pamplona,Anna M Pauter,Emanuela Talamonti,Irina G Shabalina,Tore Bengtsson

doi:10.3390/nu14030559

Abstract

The fatty acid elongase elongation of very long-chain fatty acids protein 2 (ELOVL2) controls the elongation of polyunsaturated fatty acids (PUFA) producing precursors for omega-3, docosahexaenoic acid (DHA), and omega-6, docosapentaenoic acid (DPAn-6) in vivo. Expectedly, Elovl2-ablation drastically reduced the DHA and DPAn-6 in liver mitochondrial membranes. Unexpectedly, however, total PUFAs levels decreased further than could be explained by Elovl2 ablation. The lipid peroxidation process was not involved in PUFAs reduction since malondialdehyde-lysine (MDAL) and other oxidative stress biomarkers were not enhanced. The content of mitochondrial respiratory chain proteins remained unchanged. Still, membrane remodeling was associated with the high voltage-dependent anion channel (VDAC) and adenine nucleotide translocase 2 (ANT2), a possible reflection of the increased demand on phospholipid transport to the mitochondria. Mitochondrial function was impaired despite preserved content of the respiratory chain proteins and the absence of oxidative damage. Oligomycin-insensitive oxygen consumption increased, and coefficients of respiratory control were reduced by 50%. The mitochondria became very sensitive to fatty acid-induced uncoupling and permeabilization, where ANT2 is involved. Mitochondrial volume and number of peroxisomes increased as revealed by transmission electron microscopy. In conclusion, the results imply that endogenous DHA production is vital for the normal function of mouse liver mitochondria and could be relevant not only for mice but also for human metabolism.

Highlights

The findings presented here emphasize the importance of considering the interindividual genetic variability in endogenous long-chain polyunsaturated fatty acids (PUFA) production and is relevant for both dietetics and scholars working in molecular metabolism
PUFAs are considered to play a central role in these pathologies since within the mitochondrial membrane, PUFAs are the primary cellular target of reactive oxygen species (ROS) attack and contribute to the generation of oxidatively damaged proteins [16,17,37,38]
The opposite was observed with the substantial decrease in the lipoxidation marker malondialdehyde lysine (MDAL) in the PUFA-deficient Elovl2 KO mice

Summary

Introduction

Dietary polyunsaturated fatty acids (PUFAs) have been shown to play important roles in human health, and mitochondria could be an essential component of PUFAs’ effects [1,2,3]. There is growing evidence that dietary docosahexaenoic acid (DHA) profoundly affects mitochondrial membrane phospholipid composition and mitochondrial function [1]. It has been previously shown that deficiency in other PUFAs (precursors for DHA) in the diet causes uncoupling of oxidative phosphorylation in rat liver mitochondria [4]. Impaired levels of dietary 18:2n-6 lead to decreased activity of the enzyme cytochrome c oxidase and reduced mitochondrial respiration in rat hearts [5]. The role of endogenously synthesized PUFA vs PUFA taken up from the diet is poorly investigated [6]

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Conclusion