Referencia

Proc Natl Acad Sci USA (2018). doi: 10.1073/pnas.1806833115. Imagen revista

Autores

Alejandra Guerra-Castellano, Antonio Díaz-Quintana, Gonzalo Pérez-Mejías, Carlos A. Elena-Real, Katiuska González-Arzola, Sofía M. García-Mauriño, Miguel A. De la Rosa, and Irene Díaz-Moreno.

Resumen

Respiratory cytochrome c has been found to be phosphorylated at tyrosine 97 in the postischemic brain upon neuroprotective insulin treatment, but how such posttranslational modification affects mitochondrial metabolism is unclear. Here, we report the structural features and functional behavior of a phosphomimetic cytochrome c mutant, which was generated by site-specific incorporation at position 97 of p-carboxymethyl-L-phenylalanine using the evolved tRNA synthetase method. We found that the point mutation does not alter the overall folding and heme environment of cytochrome c, but significantly affects the entire oxidative phosphorylation process. In fact, the electron donation rate of the mutant heme protein to cytochrome c oxidase, or complex IV, within respiratory supercomplexes was higher than that of the wild-type species, in agreement with the observed decrease in reactive oxygen species production. Direct contact of cytochrome c with the respiratory supercomplex factor HIGD1A (hypoxia-inducible domain family member 1A) is reported here, with the mutant heme protein exhibiting a lower affinity than the wild-type species. Interestingly, phosphomimetic cytochrome c also exhibited a lower caspase-3 activation activity. Altogether, these findings yield a better understanding of the molecular basis for mitochondrial metabolism in acute diseases, such as brain ischemia, and thus could allow the use of phosphomimetic cytochrome c as a neuroprotector with therapeutic applications.

 

Descripción

El presente trabajo describe como la disminución en la muerte neuronal post-isquemia se debe a cambios sustanciales en el metabolismo mitocondrial (incluida la menor producción de especies reactivas de oxígeno) y la homeostasis celular inducida por la fosforilación del citocromo c. Estos hallazgos, por lo tanto, proporcionan las bases para comprender el mecanismo molecular y el uso potencial de especies fosfomiméticas de citocromo c, lo que ofrece nuevas oportunidades para desarrollar terapias más eficientes contra inducidas por hipoxia aguda.

 

 

Imagen Grupo Biointeractomica

 

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo Biointeractómica centra sus esfuerzos en el análisis estructural y funcional de las macromoléculas biológicas, así como de sus interacciones, que son claves en una amplia variedad de procesos celulares. También profundiza en el estudio de las modificaciones post-traduccionales de las proteínas y, en particular, del citocromo c, proteína que juega un doble papel en la vida y muerte celular.

 Descargar el artículo 

¿Acabas de publicar un artículo interesante?

Manda la referencia a través de nuestro formulario.  Límite de edad 32 años. Los artículos seleccionados serán destacados como artículos del mes y participarán en el Premio al mejor artículo de jóvenes de la SEBBM, que se entregará en el congreso de la SEBBM (inscripción y alojamiento gratuitos).

Otros "Artículos del mes"

A Mammalian Target of Rapamycin-Perilipin 3 (mTORC1-Plin3) Pathway is essential to Activate Lipophagy and Protects Against Hepatosteatosis

24-09-2021

Background and Aims: NAFLD is the most common hepatic pathology in western countries and no treatment is currently available. NAFLD is characterized by the aberrant hepatocellular accumulation of fatty acids...

Leer más

NF-κB/IKK activation by small extracellular vesicles within the SASP

07-09-2021

Cellular senescence plays an important role in different biological and pathological conditions. Senescent cells communicate with their microenvironment through a plethora of soluble factors, metalloproteases and extracellular vesicles (EV). Although...

Leer más

α-Helical peptidic scaffolds to target α-synuclein toxic species with nanomolar affinity

28-07-2021

α-Synuclein aggregation is a key driver of neurodegeneration in Parkinson's disease and related syndromes. Accordingly, obtaining a molecule that targets α-synuclein toxic assemblies with high affinity is a long-pursued objective...

Leer más

Neutrophil infiltration regulates clock-gene expression to organize daily hepatic metabolism

30-06-2021

Liver metabolism follows diurnal fluctuations through the modulation of molecular clock genes. Disruption of this molecular clock can result in metabolic disease but its potential regulation by immune cells remains...

Leer más

G6PD overexpression protects from oxidative stress and age-related hearing loss

23-05-2021

Aging of the auditory system is associated with the incremental production of reactive oxygen species (ROS) and the accumulation of oxidative damage in macromolecules, which contributes to cellular malfunction, compromises...

Leer más

Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis

25-04-2021

Chronic kidney disease (CKD) remains a major epidemiological, clinical, and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) present a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO)...

Leer más

Astrocyte-mediated switch in spike timing-dependent plasticity during hippocampal development

29-03-2021

Presynaptic spike timing-dependent long-term depression (t-LTD) at hippocampal CA3-CA1 synapses is evident until the 3rd postnatal week in mice, disappearing during the 4th week. At more mature stages, we found...

Leer más

Ceramide chain length–dependent protein sorting into selective endoplasmic reticulum exit sites

22-02-2021

Protein sorting in the secretory pathway is crucial to maintain cellular compartmentalization and homeostasis. In addition to coat-mediated sorting, the role of lipids in driving protein sorting during secretory transport...

Leer más

Antigen retrieval and clearing for whole-organ immunofluorescence by FLASH

25-01-2021

Advances in light-sheet and confocal microscopy now allow imaging of cleared large biological tissue samples and enable the 3D appreciation of cell and protein localization in their native organ environment...

Leer más

Viral Bcl2s' transmembrane domain interact with host Bcl2 proteins to control cellular apoptosis

08-01-2021

Viral control of programmed cell death relies in part on the expression of viral analogs of the B-cell lymphoma 2 (Bcl2) protein known as viral Bcl2s (vBcl2s). vBcl2s control apoptosis...

Leer más

Socios Protectores