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

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 (DPAn6) in vivo. Expectedly, Elovl2-ablation drastically reduced the DHA and DPAn6 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.

Hacd2 deficiency in mice leads to an early and lethal mitochondrial disease

“…Our study thus confirms the role of the VLCFA elongation cycle in mitochondrial homeostasis [ 22 , 35 ]. More precisely, mitochondrial dysfunction in Hacd2 -KO embryos, and in the kidney and liver of Hacd2 -KD pups, affected both the respiratory chain complexes and respiratory coupling.…”

Integrative Analysis of Liver Metabolomics and Transcriptomics Reveals Oxidative Stress in Piglets with Intrauterine Growth Restriction

“…Moreover, alterations involving the LC-PUFA synthesis pathway causes an imbalance in the n-3/n-6 ratio and lipid peroxidation, which also leads to the production of ROS, subsequently damaging cellular functions [ 37 ]. Previous studies have found that abnormal expression of ELOVL2 and FADS2 in liver may lead to membrane fatty acid remodeling and impaired membrane lipid homeostasis [ 38 ]. In this result, the mRNA expression levels of ELOVL2 , FADS2 , ACOT7 , CYP2C , CYP4A , PTGS1 , ALOX5 , and GGT5 , which are involved in EPA and AA metabolism, were also altered in the livers of IUGR piglets.…”

A set of common buccal CpGs that predict epigenetic age and associate with lifespan-regulating genes

“…The deletion of Elovl2 reduces lifespan and induces an accelerated aging phenotype in mice characterized by early hair loss as well as impairments in bone density, endurance, muscle strength, learning, and memory ( Li et al., 2022 ). Separate work has shown that the ablation of Elovl2 drives mitochondrial dysfunction in the mouse liver ( Gomez Rodriguez et al., 2022 ). Given that the hypermethylation of this gene is tethered to a reduced expression level with age ( Chen et al., 2020 ; Li et al., 2022 ), it is feasible that the methylation of ELOVL2 contributes to age-related pathology.…”