Thursday, 5th December 2019

Cellular studies of oxidative stress and apoptosis in inherited metabolic diseases: move forward in pathophysiology and treatment





Eva María Richard







Research summary:

Inherited metabolic diseases (IMD) include a broad spectrum of biochemical alterations caused by genetic defects which affect the structure and function of proteins involved in cellular metabolic pathways. More than 700 IMD have been identified that affect the synthesis, metabolism, transport or/and storage of biochemical compounds, and they are considered rare diseases. Our main goal is to identify new modifier genes that could be considered new therapetical targets in these disorders. Emerging evidences have shown: i) that the generation of reactive oxygen species (ROS) contributes to the neurological phenotype of neurodegenerative, chronic-inflammatory and vascular diseases, and cancer; ii) that most of the patients affected by IMD predominantly present neurological symptoms and structural brain abnormalities, and iii) that our previous results have shown an increase in intracellular ROS and apoptosis levels in fibroblasts from patients with defects on cobalamin metabolism and with propionic acidemia.



DETECTION OF INTRACELLULAR ROS AND APOPTOSIS LEVELS IN FIBROBLASTS FROM METHYLMALONIC ACIDEMIA PATIENTS. Intracellular levels of ROS were detected by microscopy (A) and flow cytometry (B) using the H2DCFDA fluorescence probe. The percentage of apoptotic cells was analyzed by flow cytometry using annexin V and caspase 9 fluorescence probes. ROS levels and apoptotic cells were increased in fibroblasts from patients respect to controls. Caspase 9 activation indicates that the intrinsic or mitochondrial pathway is probably the main activated pathway in these patients.


In light of the abovementioned results, our research line at present is mainly focused on the analysis of mitochondrial dysfunction as pathophysiological mechanism and as new therapeutic target using a cellular model (patients´ fibroblasts) and an animal model (knockout PCCA). Specifically, we are analysing in patients´ fibroblasts with defects in cobalamin metabolism and with homocystinuria: i) different parameters related to oxidative stress and apoptosis, ii) mitochondrial morphology, mitochondrial respiration and the opening of mitochondrial permeability transition pore. In addition, the effects of different antioxidants are being evaluated in the cellular model that will be further analysed in the future in the animal model. The results will allow establishing a relationship with the phenotype of these patients, determining its relevance in the pathophysiology of IMD and thus opening the possibility to use antioxidant reagents to prevent cellular damage for a better life quality of the patients.



Selected publications:

Gallego-Villar L, Pérez-Cerdá C, Pérez B, Abia D, Ugarte M, Richard E, Desviat LR “Functional characterization of novel genotypes and oxidative stress cellular studies in propionic acidemia”. Journal of Inherited Metabolic Diseases DOI: 10.1007/s10545-012-9545-3 (2012).

Richard E, Desviat LR, Ugarte M, Pérez B. “Oxidative stress and apoptosis in homocystinuria patients with genetic remethylation defects”. Journal of Cellular Biochemistry 114:183-191 (2013).

Jorge-Finnigan A, Gámez A, Pérez B, Ugarte M and Richard E. “Different altered pattern expression of genes related to apoptosis in isolated methylmalonic aciduria cblB type and combined with homocystinuria cblC type”. Biochimica et Biophysica Acta-Molecular Basis of Disease 1802 (11): 959-967 (2010).

Richard E, Jorge-Finnigan A, Garcia-Villoria J, Merinero B, Desviat LR, Gort L, Briones P, Leal F, Pérez-Cerdá C, Ribes A, Ugarte M, Pérez B; MMACHC Working Group. “Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC)”. Human Mutation 30 (11): 1558-1566 (2009). 


NOTE! This site uses cookies and similar technologies.

If you not change browser settings, you agree to it. Learn more

I understand


What are cookies?

A cookie is a file that is downloaded to your computer when you access certain web pages. Cookies allow a web page, among other things, to store and retrieve information about the browsing habits of a user or their equipment and, depending on the information they contain and the way they use their equipment, they can be used to recognize the user.

Types of cookies

Classification of cookies is made according to a series of categories. However, it is necessary to take into account that the same cookie can be included in more than one category.

  1. Cookies according to the entity that manages them

    Depending on the entity that manages the computer or domain from which the cookies are sent and treat the data obtained, we can distinguish:

    • Own cookies: those that are sent to the user's terminal equipment from a computer or domain managed by the editor itself and from which the service requested by the user is provided.
    • Third party cookies: those that are sent to the user's terminal equipment from a computer or domain that is not managed by the publisher, but by another entity that processes the data obtained through the cookies. When cookies are installed from a computer or domain managed by the publisher itself, but the information collected through them is managed by a third party, they cannot be considered as own cookies.

  2. Cookies according to the period of time they remain activated

    Depending on the length of time that they remain activated in the terminal equipment, we can distinguish:

    • Session cookies: type of cookies designed to collect and store data while the user accesses a web page. They are usually used to store information that only is kept to provide the service requested by the user on a single occasion (e.g. a list of products purchased).
    • Persistent cookies: type of cookies in which the data is still stored in the terminal and can be accessed and processed during a period defined by the person responsible for the cookie, which can range from a few minutes to several years.

  3. Cookies according to their purpose

    Depending on the purpose for which the data obtained through cookies are processed, we can distinguish between:

    • Technical cookies: those that allow the user to navigate through a web page, platform or application and the use of different options or services that exist in it, such as controlling traffic and data communication, identifying the session, access to restricted access parts, remember the elements that make up an order, perform the purchase process of an order, make a registration or participation in an event, use security elements during navigation, store content for the broadcast videos or sound or share content through social networks.
    • Personalization cookies: those that allow the user to access the service with some predefined general characteristics based on a series of criteria in the user's terminal, such as the language, the type of browser through which the user accesses the service, the regional configuration from where you access the service, etc.
    • Analytical cookies: those that allow the person responsible for them to monitor and analyse the behaviour of the users of the websites to which they are linked. The information collected through this type of cookies is used in the measurement of the activity of the websites, applications or platforms, and for the elaboration of navigation profiles of the users of said sites, applications and platforms, in order to introduce improvements in the analysis of the data of use made by the users of the service.

Cookies used on our website

The CBMSO website uses Google Analytics. Google Analytics is a simple and easy to use tool that helps website owners to measure how users interact with the content of the site. You can consult more information about the cookies used by Google Analitycs in this link.

Acceptance of the Cookies Policy

The CBMSO assumes that you accept the use of cookies if you continue browsing, considering that it is a conscious and positive action from which the user's consent is inferred. In this regard, you are previously informed that such behaviour will be interpreted that you accept the installation and use of cookies.

Knowing this information, it is possible to carry out the following actions:

How to modify the configuration of cookies

Using your browser you can restrict, block or delete cookies from any web page. In each browser the process is different, here we show you links on this particular of the most used browsers: