Targeting Key Protein in CMT Type 2A May Be Basis of Future Therapies, Study Suggests

José Lopes, PhD avatar

by José Lopes, PhD |

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Researchers found that small molecules which target the key protein altered in patients with Charcot-Marie-Tooth disease type 2A (CMT2A) may be a viable therapeutic approach and also improve other diseases with impaired mitochondrial health.

The study, “MFN2 agonists reverse mitochondrial defects in preclinical models of Charcot-Marie-Tooth disease type 2A,” appeared in the journal Science.

CMT2A is caused by mutations in the MFN2 gene, which provides instructions to make MFN2, a protein involved in the structure and mobility of mitochondria (the energy-producing part of cells), which are essential processes for healthy cells.

MFN2 is a dynamic protein and switches between closed and open conformations, depending on how closely its two domains, or sections, interact. The open conformation promotes mitochondrial fusion and can be induced by a peptide matching a small sequence of amino acids – the building blocks of proteins – of MFN2.

Mitochondria are dynamic structures and undergo either fusion or fission depending on the needs of the cell.

The scientists conducted experiments in genetically engineered cells without the proteins MFN2 or MFN1, which is also critical for mitochondrial health.

They observed that forcing the production of normal (or wild-type) MFN2 restored the mitochondria’s length and fusion. However, promoting the production of an enzyme called PINK1 blocked these events.

The team then tested small molecules for their ability to promote mitochondrial fusion. They focused on those with identical amino acid sequences as mini-peptides with the critical serine at both phosphorylated (class A) and unphosphorylated (class B) states.

Phosphorylation is a process that alters the conformation of a protein, leading to its activation, deactivation, or changing its function.

Researchers hypothesized that adding both class A and B MFN1/2 agonists (activators) would increase mitochondrial fusion by acting on the two phosphorylation states.

After confirming their hypothesis, they created a new molecule combining class A and B features, called chimera B-A. This new molecule significantly induced mitochondrial fusion in cells without MFN2 and effectively reversed the changes in mitochondrial shape, called dysmorphometry, in neurons from mice with CMT2A.

Additional analyses revealed that these small molecules favored mitochondrial fusion by stabilizing an open conformation of MFN1 or MFN2.

Experiments in cells derived from mice demonstrated that small MFN1/2 agonists were only able to restore mitochondrial shape and function in mutant MFN2 when MFN1 was present.

Because MFN2 also regulates mitochondrial mobility along nerve fibers critically involved in CMT2A, the scientists evaluated the effects of these small MFN agonists in mitochondrial mobility. They found that the chimera B-A protein molecules restored mitochondrial mobility and normal shape in CMT2A mutant cells.

Then, in mice with CMT2A, researchers observed that the chimera B-A protein restored mitochondrial mobility in the sciatic nerve.

“We developed a novel small-molecule [MFN] agonist that reversed the neuronal mitochondrial dysmorphometry [abnormal shape] and impaired mobility evoked by two CMT2A Mfn2 mutants,” the researchers wrote.

Besides its potential applicability for future CMT2A therapies, researchers hypothesized that patients with Alzheimer’s, Parkinson’s, and Huntington’s disease may also benefit from these findings.