sabato, Luglio 13, 2024

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Antioxidants: not all of them match for mitochondrial needs

Mitochondria are tiny structures in human and animal cells that produce energy through an integrated series of chemical reactions known as the respiratory chain (RC). Mitochondria contain their own DNA, distinct from the more familiar DNA inside a cell nucleus. Because pathogenic variants in over 350 different genes across both nuclear and mitochondrial DNA genomes are now recognized to cause mitochondrial diseases, these disorders are highly complex, typically causing 16 or more symptoms per patient, and affecting multiple organs and systems. Much of the damage in mitochondrial diseases stems from oxidative stress, in which reactive molecules disrupt energy-producing components inside the mitochondrial RC. Antioxidant compounds, by acting to defend against these free radicals, may offer some protection from mitochondrial dysfunctions. Indeed, new preclinical findings from extensive cell and animal studies suggest that a drug already used for a rare kidney disease could benefit patients with some mitochondrial disorders–complex conditions with severe energy deficiency for which no proven effective treatments exist.

Marni J. Falk, MD, at Children’s Hospital of Philadelphia (CHOP), the Executive Director of CHOP’s Mitochondrial Medicine Frontier Program, led the research. She explained: “We found therapeutic potential in mitochondrial disease, based on evidence for neuroprotection in two different animal models. However, we also showed that this drug has a narrow therapeutic window–even small increases in dosage were toxic in diverse laboratory animals and human cells. This implies that dosages would need to be very carefully controlled if cysteamine bitartrate (CYB) eventually were to become a precision medicine treatment option for mitochondrial disease patients. Future clinical research is needed to explore whether the drug, cysteamine bitartrate, will meaningfully benefit patients”. Falk and colleagues have been systematically evaluating a variety of drug candidates in search of possible treatments for mitochondrial RC disease. They recently found, for instance, that the common antioxidant called NAC (short for N-acetylcysteine), commonly used for cold symptoms and able to restore oxidative stress in many cell types, showed encouraging preclinical results in animal studies.

Because cysteamine bitartrate, currently approved by the FDA to treat a rare kidney disorder called nephropathic cystinosis, was thought to act on biological pathways similarly to NAC, Falk’s team performed their current preclinical research study. They tested the hypothesis that CYB would increase synthesis of glutathione, the main cellular antioxidant that humans and animals naturally produce to scavenge free radicals. Surprisingly, they learned that CYB did not increase total glutathione levels in their experiments. However, the molecule had beneficial health effects that appear to result from different mechanisms. The researchers found an intriguing set of different benefits in three models of mitochondrial disease: human patient cells (fibroblasts), microscopic worms (C. elegans) and microscopic fish (zebrafish). Cysteamine bitartrate modestly improved mitochondrial metabolism and reproductive capacity in the worms, with reduction in oxidative stress. In the zebrafish, the drug had more dramatic benefits, preventing brain death and neuromuscular defects caused by mitochondrial RC dysfunction.

In the human fibroblast cells, from mitochondrial disease patients, the drug increased the cells’ resiliency and ability to survive when subjected to chemical stressors. Overall, treatment effects observed in both cell and animal models of mitochondrial RC disease suggest that CYB might have the potential to improve overall health and stress resiliency in human patients. In previous experiment last year, Dr. Falk and her team tested cellular antioxidants like lipoic acid, coenzyme Q, NAC, vitamin E, orotate and vitamin C in lab models for RC disorders. While vitamin E and NAC were able to fully reverse the metabolic and oxidative problems, the other antioxidants had only partial effects. That is why Dr. Falk cautioned that patients and families shouldn’t self-prescribe antioxidants for mitochondrial disease, since safe and effective dosages and appropriate usages specific to different mitochondrial disease patient outcomes are yet to be determined. In this current study, all the potential benefits observed in cells and animals occurred at low concentrations, with clear toxicity at higher doses.

Identifying the right kinds of antioxidant treatments at the proper dosage may be neuroprotective, potentially preventing metabolic strokes that often occur when mitochondrial disease patients are stressed by an infection or other risk factors. She concluded: “Now that preclinical evidence is increasing to support the potential of antioxidant therapies to objectively benefit overall health in the setting of RC disease, better clinical tests are needed to evaluate oxidant levels and antioxidant enzyme activities, as well as mitochondrial function and clinical outcomes, in patients who receive antioxidant therapy. Ultimately, better understanding each mitochondrial disease patient’s oxidative stress and defense levels, together with carefully designed clinical trials to determine the health benefits or risks of candidate therapies, will enable a precision mitochondrial medicine approach to select optimal antioxidants and doses to improve health resiliency and outcomes for each patient”.

The study team published its findings in the journal Human Molecular Genetics.

  • Edited Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Guha S, Konkwo C et al., Falk MJ. Hum Mol Genet. 2019 Jan 22. 

Zolkipli-Cunningham Z et al. PLoS One. 2018 May; 13(5):e0197513. 

Polyak E et al., Falk MJ. Mol Genet Metab. 2018 Apr;123(4):449-462. 

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Dott. Gianfrancesco Cormaci
Dott. Gianfrancesco Cormaci
Laurea in Medicina e Chirurgia nel 1998, specialista in Biochimica Clinica dal 2002, ha conseguito dottorato in Neurobiologia nel 2006. Ex-ricercatore, ha trascorso 5 anni negli USA alle dipendenze dell' NIH/NIDA e poi della Johns Hopkins University. Guardia medica presso la casa di Cura Sant'Agata a Catania. In libera professione, si occupa di Medicina Preventiva personalizzata e intolleranze alimentari. Detentore di un brevetto per la fabbricazione di sfarinati gluten-free a partire da regolare farina di grano. Responsabile della sezione R&D della CoFood s.r.l. per la ricerca e sviluppo di nuovi prodotti alimentari, inclusi quelli a fini medici speciali.

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