Adenosine able to boost function of mitochondria in FA cell study

Molecule could serve promising role in breakthrough treatments

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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An illustration of mitochondria.

A naturally occurring molecule known as adenosine was found to improve the mitochondrial function in cells called fibroblasts from a Friedreich’s ataxia (FA) patient.

Mitochondria are structures often dubbed the powerhouses of the cell, as they play an essential role in producing energy. Mitochondrial dysfunction is a hallmark of FA.

Adenosine could serve as “a promising therapeutic associated with mitochondrial dynamics that could eventually be a major breakthrough in the treatment of Friedreich’s ataxia,” researchers suggest.

The study, “Adenosine Improves Mitochondrial Function and Biogenesis in Friedreich’s Ataxia Fibroblasts Following L-Buthionine Sulfoximine-Induced Oxidative Stress,” was published in the journal Biology.

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Lack of frataxin affects mitochondria functioning

FA is caused by deficient production of frataxin, a key protein for mitochondria functioning. The nervous system and muscles are particularly affected.

Lack of frataxin is associated with impaired energy production and oxidative stress — when the production of harmful molecules called reactive oxygen species outweighs the body’s antioxidant defenses.

Adenosine is widely distributed in the central nervous system where it plays a variety of functions, such as regulating the release of neurotransmitters (chemical messengers that carry chemical signals from one neuron to the next target cell) and the activity of neurons.

Previous studies showed that adenosine exerts a protective effect against cerebellar ataxia, a specific type of ataxia (poor muscle control resulting in clumsy voluntary movements) that is caused by damage to the cerebellum.

In the study, a team from Malaysia and China hypothesized that adenosine could help ease the dysfunction of mitochondria in FA.

They used fibroblasts, a type of connective tissue cell, derived from the skin of a 30-year-old man with FA and from a healthy man, who served as a control.

Our study demonstrated that adenosine targeted mitochondrial defects in FRDA [FA]. Therefore, we suggest a possible therapeutic role for adenosine in FRDA.

Fibroblasts treated with increasing doses of adenosine

The fibroblasts were treated with increasing doses of adenosine. Doses up to 800 micromolar led to no significant differences in cell viability compared to the control and were used in follow-up experiments.

To induce oxidative stress, the cells were treated with L-buthionine sulfoximine (BSO). The researchers then assessed mitochondrial function by evaluating the mitochondrial membrane potential (MMP), an indicator of mitochondrial activity.

BSO significantly reduced MMP from 100% to 87.86% when compared to untreated cells. However, in cells pre-incubated with adenosine, MMP significantly increased compared to cells treated with the antioxidant idebenone — which served as positive controls — or BSO alone.

The activity of aconitase, a key enzyme in energy production by mitochondria, was reduced to 59.33% in cells given BSO. Pre-treatment with adenosine did not restore aconitase activity, but its effects (at doses of 400 and 600 micromolar) were superior to idebenone in boosting aconitase activity.

ATP — the molecular currency of energy in cells — was also reduced by BSO to 74.83%, but pre-treatment with 200 micromolar of adenosine restored ATP levels to 85.45%. Compared to idebenone, adenosine had a significantly superior effect in increasing ATP levels.

Adenosine also improved the generation of new mitochondria, as measured by the ratio of two of its proteins, called SDH-A and COX1. Compared to BSO alone, adenosine at 400 micromolar increased the SDH-A/COX1 ratio to 109.77%, and at 600 micromolar to 108.32%. All adenosine doses led to a 2.1- to 2.2-times greater increase in the SDH-A/COX1 ratio compared to idebenone.

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Researchers study gene activity related to mitochondria

Next, the researchers investigated the expression (activity) of genes related to the growth and division of mitochondria, which generates new mitochondria.

NFR1 gene expression was significantly increased by 2.6 times in BSO-treated cells, but pre-incubation with adenosine at 400 and 600 micromolar significantly decreased it. Similar results were obtained for the TFAM gene.

The NFE2L2 gene regulates several antioxidant genes, as well as anti-inflammatory and metabolic enzymes, whereas the PPARGC1A gene is a master regulator of mitochondrial generation and energy expenditure.

The expression of NFE2L2 increased by 13.5 times with BSO compared to untreated cells, but adenosine at 600 micromolar decreased it by 79.6 times relative to BSO. In addition, BSO did not affect the expression of PPARGC1A and no reduction was observed with adenosine pre-treatment.

“Our study demonstrated that adenosine targeted mitochondrial defects in FRDA [FA],” the scientists wrote. “Therefore, we suggest a possible therapeutic role for adenosine in FRDA.”