Metab1 | Main Goals

Ageing constitutes a major risk factor for late-onset neurodegenerative diseases, such as Alzheimer’s (AD) and Parkinson’s diseases (PD), and cardiovascular and metabolic disorders, such as type 2 diabetes. Accumulating evidence shows that deficits in glucose metabolism, mitochondrial dysfunction, oxidative stress and deregulation of protein homeostasis (proteostasis) play a key role in ageing and several age-related pathologies by affecting different cell types and cell-cell communication.

Alterations of mitochondrial redox status, dynamics (fission, fusion, transport and mitophagy) and biogenesis and defects in mitochondrial-associated membranes (MAMs) have been observed in various metabolic disorders, including diabetes, ageing and age-related neurodegenerative and cardiovascular diseases. However, the mechanisms responsible for mitochondrial changes and the pathways leading to metabolic disturbances remain to be defined.
Failures in quality control, which is vital for maintaining a fully functional cell, are intimately associated with energetic deficits and are involved in multiple pathological processes, likely representing a fundamental factor in ageing. In fact, ageing and neurodegenerative, cardiovascular and metabolic disorders are characterized by an accumulation of misfolded and aggregated proteins and dysfunctional organelles that potentiates cells’ degeneration and death, culminating in organs malfunction. Besides energy deficits, other events such as redox status, protein acetylome, lipid signaling and inappropriate exosome-mediated intercellular communication may underlie the failure of the quality control pathways (e.g. unfolded protein response, ubiquitin-proteasome system, autophagy). However, the mechanistic basis for these defects and how they impact cellular homeostasis remain poorly understood.

Under this perspective and based on our previous findings we will tackle the following questions:

1. How mitochondrial dynamics and biogenesis alterations and mitochondria-endoplasmic reticulum (ER) miscommunication affect synapses and neurons in ageing, diabetes and Alzheimer’s (AD) and Parkinson’s (PD) diseases?;

2. How lipid transfer between mitochondria and ER through MAM affects synaptic and neuronal function in ageing, diabetes and age-related disorders?;

3. Are type 2 diabetes (T2D)-associated mitochondrial defects (signals and dynamics) involved in the increased risk for AD, PD and other age-related neurodegenerative disorders?;

4. How mitochondrial dysfunction impact intracellular trafficking and quality control mechanisms through protein acetylome changes in ageing, AD and PD?;

5. Are disturbances in quality control a trigger for inflammasome activation in ageing (inflammaging) and age-related disorders?;

6. Can mitochondrial, ER and autophagy modulators overcome the defects observed during ageing and development of age-related metabolic, neurodegenerative and cardiovascular diseases?;

7. How intercellular communication deregulation, namely via miRNA-containing exosomes, affect the neurovascular unit and cardiovascular function during ageing and age-related diseases? Can impaired proteostasis be a trigger of this deregulation?

Our research involves several experimental models including mitochondrial-DNA depleted and hybrid cell lines, dendritic cells, primary cell cultures and cell lines, isolated mitochondria, tissue homogenates and slices obtained from several animal models and human tissues and peripheral samples.

Our know-how, together with our (inter)national collaborations, provide excellent guarantees for the prosecution of a research translational strategy that may accelerate the bench to bedside transfer of knowledge.