Generate neurons by direct reprogramming of skin cells from patients with MELAS syndrome


The Rare Diseases Network Biomedical Research Center (CIBERER) has described the generation of neurons by direct reprogramming of skin cells from patients with mitochondrial encephalomyopathy syndrome, lactic acidosis and stroke-like episodes (MELAS).

This study will allow a better understanding of the pathological mechanisms of the disease and the evaluation of potential treatments.

Mitochondrial diseases are a heterogeneous group of rare genetic disorders caused by mutations in nuclear or mitochondrial DNA (mtDNA). These diseases are frequently multisystemic, although they mainly affect tissues that require large amounts of energy, such as the brain.

Mutations in mitochondrial transfer RNA (mt-tRNA) lead to defects in protein translation that can compromise some or all of the proteins encoded by mtDNA.

Currently, there are no curative treatments for MELAS syndrome, so it is necessary to develop models of the disease that allow the search for effective therapies.

Due to the lack of suitable animal models, several cellular models have been developed to study the disease, providing insights into the pathophysiological mechanisms of MELAS.

The authors of this work, published in ‘Cellular Reprogramming’, show a successful direct conversion of fibroblasts derived from MELAS patients into induced neurons.

The generated neurons maintain the mutation present in fibroblast skin cells and, co-cultured with astrocytes (support cells that provide nutrition, support and protection to neurons), show electrophysiological properties. Therefore, direct reprogramming is a promising strategy for studies of mitochondrial diseases and its use for drug screening.


Mitochondrial diseases encompass a wide spectrum of chronic and progressive muscle and neurodegenerative disorders caused by mutations in nuclear (nDNA) or mitochondrial (mtDNA) DNA, most of which have no effective treatment. These diseases are highly heterogeneous and fundamentally affect the energy production capacity of cells.

Current pharmacological therapies are fundamentally based on: eliminating toxic metabolites; attempt to bypass respiratory chain blockages; administer metabolites and cofactors to improve ATP synthesis, and prevent oxidative stress.

Given the diversity of mutations and the different therapeutic options, the ‘Mitocure Platform’ proposal defends that, in mitochondrial diseases, a personalized therapeutic approach is mandatory.

With this platform, researchers from the Pablo de Olavide University (UPO) evaluate the therapeutic effectiveness of the different treatments available in fibroblasts derived from mitochondrial patients and in neuronal cells generated by direct reprogramming.

To achieve this goal, they study the effects of these treatments on the pathophysiological alterations present in fibroblasts and neuronal cells derived from patients in a personalized way.

In cellular models, they study cell proliferation and/or cell death in a medium containing galactose (which forces the mitochondria to obtain energy), the enzymatic activities of the mitochondrial respiratory chain, the expression levels of mitochondrial proteins, the potential of the mitochondrial membrane, and the activation of mitochondrial degradation and/or apoptosis.

Currently, the ‘Mitocure platform’ is performing personalized precision measurement on more than 30 mutations that directly or indirectly affect energy formation by mitochondria.

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