Lumacaftor Leads to ‘Healthy Cell’ Protein Reorganization in Organelles

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Lumacaftor (VX-809) — one of the medications in the CFTR modulator Orkambi —  led to a significant protein reorganization in two cellular compartments in a cell model of cystic fibrosis (CF), causing them to more closely resemble healthy cells, a study showed.

The findings expand the potential mechanisms by which lumacaftor exerts its therapeutic effects in CF, the researchers noted.

The study, “CFTR Rescue by Lumacaftor (VX-809) Induces an Extensive Reorganization of Mitochondria in the Cystic Fibrosis Bronchial Epithelium,” was published in Cells. 

CF is caused by mutations in both copies of the CFTR gene, which is responsible for making a protein of the same name. Normally, the CFTR protein is transported to the cell surface, where it regulates the flow of ions across the cell membrane.

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Scientists Figure Out How Tezacaftor, Lumacaftor Interact With CFTR

While each mutation affects the protein differently, the most common mutation, called F508del, results in a misfolded, partially functional CFTR protein that’s broken down before it can travel to the cell surface.

Lumacaftor is part of Orkambi (lumacaftor/ivacaftor), a CFTR modulator marketed by Vertex Pharmaceuticals and available for CF patients with two copies of the F508del mutation. CFTR modulators are designed to improve the functionality of the mutated CFTR.

Known as a CFTR corrector, lumacaftor works by helping the CFTR protein acquire the right shape, restoring its transportation to the cell surface, where it can exert its role, at least to some level.

Although known to act on CFTR itself, whether lumacaftor treatment also affects other proteins within the cell is not known.

Researchers in Italy and the U.K. evaluated the effects of lumacaftor in lab-grown human airway cells producing the F508del-mutated CFTR. The goal was to assess changes in the levels and localization of proteins other than CFTR.

Results showed that 24 hours of treatment induced no dramatic changes in the overall levels of all of the 3,432 evaluated proteins. However, the researchers did identify some changes to the localization of 45 proteins.

Specifically, they found that 24 of these appeared to move to and from the mitochondria — a cellular compartment where energy is produced — after treatment with lumacaftor.

While problems in mitochondrial functions have been shown to occur in CF, 13 of these proteins have not been previously linked to the disease or treatment with CFTR modulators, the researchers noted.

Looking more closely at the cells’ mitochondria, the team found that these organelles were more compact and densely localized in mutant cells than in healthy cells, but lumacaftor treatment partially restored the shape, structure, and function of these cellular powerhouses.

The team also found that a protein called PEX13 moved from undefined locations to another cellular compartment, called the peroxisome, upon lumacaftor treatment. PEX13 is critical for the development of peroxisomes, which contain enzymes involved in several key metabolic pathways.

While mutant cells had a higher number of peroxisomes and higher PEX13 levels compared with healthy cells, lumacaftor treatment reduced the peroxisome total and the number of such organelles producing PEX13, more closely resembling healthy cells.

These changes in mitochondria and peroxisomes were most likely due to lumacaftor’s effects on CFTR, and not due to interactions with other proteins, analyses indicated.

The findings were largely confirmed in lab-grown airway cells collected from CF patients and people without the disease.

“Our data suggest additional rescue mechanisms of [lumacaftor] beyond the correction of aberrant folding of F508del-CFTR and subsequent trafficking to the [cell membrane],” the researchers wrote.

They noted that their approach offers new ways to look at how some proteins might contribute to CF by looking beyond protein levels and exploring where in the cell they’re localized.

“This new perspective will aid research into the mechanisms of pharmacological intervention for this debilitating disease,” the researchers said.