1- Effects of androgens, estrogens, and sex differences over mitochondria.

We use a great variety of cellular and molecular methods to address the hormonal regulation of signalling cascades impacting over mitochondrial function and integrity. Mostly important is to assess this response in each sex, as the expression/level of mitochondrial proteins is different in males vs females. For this, we use proteome and transcriptome profiling of male and female astrocytes and whole-brain homogenates to better understand how both, the sex and hormones, might affect the outcome in mitochondrial response to damage. 

 

Tibolone and testosterone preserve cell morphology and mitochondrial content, respectively, in astrocytic cells under glucose withdraw.

 

One of the main milestones of our group was the discovery that tibolone, a synthetic steroid drug currently in use by women to alleviate symptoms associated with menopause, is able to upregulate neuroglobin. Our group has previously reported tibolone preserves mitochondrial membrane potential, reduces oxidative stress and improves cell survival following metabolic dysfunction in glial cells. Indeed, from our previous studies, tibolone has been shown to have anti-inflammatory, antioxidant and anti-apoptotic actions, making it a suitable drug for repurposing in neurometabolic diseases including traumatic brain injury.

Tibolone exerts neuroprotective actions mediated by estrogen receptors (Del Río et al., 2020).

Neuroglobin is currently the subject of many studies in our laboratory given its immense therapeutic potential to protect both neurons and astrocytes from traumatic damage to the brain. We use several pharmacological approaches and therapies in cultured astrocytes, neurons and microglia to induce neuroglobin for mitochondrial protection. Our key aim now is to delve into the molecular mechanisms of neuroglobin signaling in male and female cells. 

 

3D structure of human neuroglobin.

We use network pharmacology for the study of protein-protein interaction networks to explore druggable cellular targets involved in traumatic brain injury and also for the identification of hubs that can become drivers in this pathology.

Interleukin-6 (IL6) as a hub regulated by tibolone and involved in traumatic brain injury pathology (McGovern and Barreto, 2021).