Biology subjects

Gonzalez-Garcia, P.

Publications and source records attributed to Gonzalez-Garcia, P..

3 recordsLinked to original sources

bioRxiv2024

Time-resolved mitochondrial-focused screening identifies regulatory components of oxidative metabolism

Defects in mitochondrial oxidative metabolism contribute to various genetic inherited disorders, termed mitochondrial diseases, with limited treatment options. Given the lack of functional annotation for numerous mitochondrial proteins, there is a necessity for an extensive gene inventory related to mitochondrial function, with special interest in Oxidative Phosphorylation (OXPHOS). To address this gap, we developed a CRISPR/Cas9 loss-of-function library targeting nuclear-encoded mitochondrial genes and conducted galactose-based screenings at various time points to uncover novel regulators of mitochondrial function. Our study resulted in a gene catalog essential for mitochondrial oxidative metabolism, and constructed a dynamic timeline mapping a broad network of mitochondrial pathways, with a particular focus on the OXPHOS complexes. Computational analysis pinpointed RTN4IP1 and ECHS1 as key genes strongly associated with OXPHOS and whose mutations are associated with mitochondrial diseases in humans. RTN4IP1 was found to be crucial for mitochondrial respiration, with complexome profiling revealing its role as an assembly factor required for the complete assembly of complex I. Furthermore, we discovered that ECHS1 controls oxidative metabolism independently of its canonical function in fatty acid oxidation. Deletion of ECHS1 leads to reduced catabolism of branched-chain amino acids (BCAAs), which impairs the activity of lipoic acid-dependent enzymes such as pyruvate dehydrogenase (PDH). This deleterious phenotype can be rescued by restricting valine intake or catabolism in ECHS1-deficient cells.

molecular biology↗

bioRxiv2023

Intratumoral injection of melatonin enhances tumor regression in cell line-derived and patient-derived xenografts of head and neck cancer by increasing mitochondrial oxidative stress

Head and neck squamous cell carcinoma present a high mortality rate. Melatonin has been shown to have oncostatic effects in different types of cancers. However, inconsistent results have been reported for in vivo applications. Consequently, an alternative administration route is needed to improve bioavailability and establish the optimal dosage of melatonin for cancer treatment. On the other hand, the use of patient-derived tumor models has transformed the field of drug research because they reflect the heterogeneity of patient tumor tissues. In the present study, we explore mechanisms for increasing melatonin bioavailability in tumors and investigate its potential as an adjuvant to improve the therapeutic efficacy of cisplatin in the setting of both xenotransplanted cell lines and primary human HNSCC. We analyzed the effect of two different formulations of melatonin administered subcutaneously or intratumorally in Cal-27 and SCC-9 xenografts and in patient-derived xenografts. Melatonin effects on tumor mitochondrial metabolism was also evaluated as well as melatonin actions on tumor cell migration. In contrast to the results obtained with the subcutaneous melatonin, intratumoral injection of melatonin drastically inhibited tumor progression in HNSCC-derived xenografts, as well as in patient-derived xenografts. Interestingly, intratumoral injection of melatonin potentiated CDDP effects, decreasing Cal-27 tumor growth. We demonstrated that melatonin increases ROS production and apoptosis in tumors, targeting mitochondria. Melatonin also reduces migration capacities and metastasis markers. These results illustrate the great clinical potential of intratumoral melatonin treatment and encourage a future clinical trial in cancer patients to establish a proper clinical melatonin treatment.

cancer biology↗

bioRxiv2021

β-RA targets mitochondrial metabolism and adipogenesis, leading to therapeutic benefits against CoQ deficiency and age-related overweight

Primary mitochondrial diseases are caused by mutations in mitochondrial or nuclear genes, leading to abnormal function of specific mitochondrial pathways. Mitochondrial dysfunction is also a secondary event in more common pathophysiological conditions, such as obesity and metabolic syndrome. In both cases, the improvement and management of mitochondrial homeostasis remains challenging. Here, we show that beta-resorcylic acid ({beta}-RA), a natural phenolic compound, competes in vivo with 4-hydroxybenzoic acid, the natural precursor of Coenzyme Q biosynthesis. This leads to a decrease of demethoxyubiquinone, an intermediate metabolite of CoQ biosynthesis that is abnormally accumulated in Coq9R239X mice. As a consequence, {beta}-RA rescues the phenotype of Coq9R239X mice, a model of primary mitochondrial encephalopathy. Moreover, we observe that long-term treatment with {beta}-RA also reduces the size and content of the white adipose tissue (WAT) that is normally accumulated during aging in wild-type mice, leading to a prevention of hepatic steatosis and an increase in survival at the old stage of life. The reduction in WAT content is due to a decrease in adipogenesis, an adaptation of the mitochondrial proteome in the kidneys, and a stimulation of glycolysis and acetyl-CoA metabolism. Therefore, our results demonstrate that {beta}-RA acts through different cellular mechanisms, with effects on mitochondrial metabolism, and it may be used for the treatment of primary Coenzyme Q deficiency, overweight, and hepatic steatosis.

physiology↗