Journal News

ELOVL4 mutations: Two sides of the same coin

Andrea Pereyra
April 18, 2023

Fatty acids constitute cellular membranes, fuel energy production and act as signaling molecules. Long-chain fatty acids have tails of 13 to 21 carbons. The enzymes known as ELOVLs — short for “elongation of very long” — can extend these tails to make them into very long-chain saturated and very long-chain unsaturated fatty acids, known respectively as VLC-SFAs and VLC-PUFAs. Defects in the elongation of fatty acids can cause neuronal, ocular and skin problems.

Researchers transduced wild-type cells (top row) and those with mutations that can affect the brain and skin (middle and bottom) with MYC-ELOVL4 constructs, immunostained them for the transcription factor MYC (red) and the endoplasmic reticulum chaperone calnexin (green), then merged them (left column).
Gyening et al./JLR
Researchers transduced wild-type cells (top row) and those with mutations that can affect the brain and skin (middle and bottom) with MYC-ELOVL4 constructs, immunostained them for the transcription factor MYC (red) and the endoplasmic reticulum chaperone calnexin (green), then merged them (left column).

Martin-Paul Agbaga, an assistant professor of cell biology and ophthalmology at the University of Oklahoma Health Sciences Center, studies the intersection between very long-chain fatty acids and human disease. In a recent publication in the Journal of Lipid Research, Agbaga and his team, which included Yeboah Kofi Gyening, described the mechanisms by which specific ELOVL4 mutations affect particular tissues.

“We are trying to figure out why some patients with ELOVL4 mutations only have retinal dysfunction, some only have brain dysfunction, and some only have skin dysfunction,” Gyening, a recent Ph.D. graduate, said. “We are basically asking why the same mutation is causing such diverse phenotypes.”

The team studied how two ELOVL4 mutants, one associated with brain disorders and the other with  skin disease in humans, elongate a precursor fatty acid. They found that both these mutations had some limited capacity to elongate PUFA precursors to VLC-PUFA but blunted the enzyme’s capability to biosynthesize VLC-SFAs.

The question of how the same ELOVL4 can synthesize different VLCFAs in different tissues remains unanswered. “You can get some clues from fish,” Gyening explained. “Some fish species have two different ELOVL4 isoforms: ELOVL4a, which is more active in elongating VLC-SFAs, and ELOVL4b, which prefers VLC-PUFAs. Something similar could happen in humans, but we don’t know yet.”

In normal tissue, ELOVL4 is found in a cell’s endoplasmic reticulum, or ER, but these authors also found it in the nuclear fraction.

The team wondered whether ELOVL4-related disease results solely from a decline in certain VLC-SFAs or if mutated protein within the cells also plays a role. “We did some experiments that indicate that ELOVL4 mutants can induce ER stress,” Gyening said, “which could explain cell death observed in the cerebellum of some patients.”

These findings also could help determine treatment for patients with ELOVL4 deficiency. “In the lab, we were able to artificially synthesize VLCFAs to incorporate into the diet of rodents carrying ELOVL4 mutations, resulting in a partial rescue of the phenotype,” Gyening said. “Because we know which VLCFAs go down with the different ELOVL mutations, we could recommend personalized dietary supplementations as part of the treatment.”

Enjoy reading ASBMB Today?

Become a member to receive the print edition monthly and the digital edition weekly.

Learn more
Andrea Pereyra

Andrea S. Pereyra is a postdoctoral scholar at the East Carolina Diabetes and Obesity Institute. She earned her M.D./Ph.D. at Universidad Nacional de La Plata in Buenos Aires, Argentina. 

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

Cows offer clues to treat human infertility
Journal News

Cows offer clues to treat human infertility

April 23, 2024

Decoding the bovine reproductive cycle may help increase the success of human IVF treatments.

Immune cells can adapt to invading pathogens
News

Immune cells can adapt to invading pathogens

April 20, 2024

A team of bioengineers studies how T cells decide whether to fight now or prepare for the next battle.

Hinton lab maps structure of mitochondria at different life stages
Member News

Hinton lab maps structure of mitochondria at different life stages

April 20, 2024

An international team determines the differences in the 3D morphology of mitochondria and cristae, their inner membrane folds, in brown adipose tissue.

National Academies propose initiative to sequence all RNA molecules
News

National Academies propose initiative to sequence all RNA molecules

April 19, 2024

Unlocking the epitranscriptome could transform health, medicine, agriculture, energy and national security.

From the journals: JLR
Journal News

From the journals: JLR

April 19, 2024

What can you do with artificial lipoproteins? A new key to angiogenesis. Flavonoids counteract oxidative stress. Read about recent papers on these topics.

Iron could be key to treating a global parasitic disease
Journal News

Iron could be key to treating a global parasitic disease

April 16, 2024

A study has found that leishmaniasis causes body-wide changes in iron balance, leading to red blood cell damage.