Pla-Martín, David - CAP 25

Mitochondria, as a central hub for metabolism, are affected in a wide variety of human diseases and during normal ageing, where mtDNA integrity is often compromised. Mitophagy, the selective removal of mitochondria, has been investigated extensively as an important salvage pathway to remove dysfunctional mitochondria. Impairment of mitophagy has been related to several important neurological diseases such as Parkinson´s, Charcot-Marie-Tooth (CMT) and other age-related syndromes. Our lab has been interested in deciphering the molecular mechanisms which determine the specificity of mitochondrial quality control. On one hand, we are interested on autophagy-related quality control pathways for mtDNA. On the other side, we explore the role of mitochondria-ER contact sites in the regulation of mitochondrial turnover. In both cases, we use disease models to understand how dysregulation of mitochondrial quality control pathways leads to disease progression.

1. Quality control mechanisms of the mtDNA

Mutations in mtDNA, packaged into nucleoids, cause severe neuro-muscular diseases, contribute to the rearrangement of metabolism in some cancers, and accumulate in many tissues as one of the hallmarks of ageing. mtDNA is present in thousands of copies per cell, therefore impairment of mitochondrial function is only observed when the percentage of mutated molecules surpasses a specific threshold. Besides the classical functions of mitochondria in metabolism, Ca²⁺ handling and apoptosis, mitochondria are now considered as central hubs in regulating inflammatory response. Disruption of mitochondrial integrity triggers mtDNA release into the cytosol which is recognized by the inflammasome, promoting the activation of pro-inflammatory cytokines and interferons. Alternatively, mtDNA has been found in the endosomal compartment, where it can also start a signaling cascade that ultimately leads to the expression of proinflammatory factors, as an indicator of mitochondrial dysfunction. How mtDNA is transferred to the endosomal compartment and the physiological role of this, is unclear.

To identify molecular partners involved in mtDNA removal, we have used APEX2 - spatial proteomics and detected the sphere of influence of nucleoids containing mtDNA mutations. We found that mtDNA damage triggers mitochondrial membrane reorganization and accumulation of endosomes in the vicinity of mitochondria. In general, we found that integrity of the mtDNA is surveyed by a new quality control mechanism involving mitochondria and endo-lysosomal contact sites. We propose that fine-tuning the activity of such proteins could be used as a therapeutic strategy against mtDNA related diseases, either inherited, acquired or due to normal ageing.

2. Mitochondria Associated membranes as a signalling hub for mitochondrial turnover.

Charcot-Marie-Tooth (CMT) is the most common inherited neurological disorder affecting 1 to 4 of 10,000 inhabitants. GDAP1 is located in the mitochondrial outer membrane and in the mitochondria associated membranes fraction (MAM, mitochondria-Endoplasmic Reticulum contact sites) where it functions as a Ca²⁺modulator. Recently, GDAP1 has been described to facilitate mitochondria-lysosome contact sites, suggesting a role in mitochondria quality control.  Using spatial proteomics, we would like to emphasize on the specific mechanisms governing mitochondrial turnover related to GDAP1. If GDAP1 is a mitophagy receptor, why is it expressed only in neuronal tissues and not in others? What triggers GDAP1 to start mitochondrial turnover?

Our research line is important for fundamental mitochondrial biology, and also to understand mitochondrial diseases and ageing. We aim to transfer our knowledge, from the basic molecular mechanisms assuring appropriate mitochondrial quality control, to design strategies against mitochondrial syndromes using screening techniques, cell and animal models.

Our Aims

Increasing evidence supports the idea that degradation of mitochondria is a highly controlled process with multiple pathways, which depend on specific proteins or mitochondrial components selected for degradation. Mitochondria and the ER cooperate to induce mitochondrial fission, necessary to initiate mitophagy. My work aims to understand the selectivity of mitophagy and how it influences severe human diseases.

• Project 1. Selective degradation of mitochondrial components and physiological consequences of dysfunction.
  1A. Selective degradation of mtDNA: with this project, we aim to decipher the specificities governing selective degradation of mtDNA bearing mutations.
  1B. Role of Mitochondria Associated Membranes (MAMs) in mitochondrial quality control and human diseases: using GDAP1 and Charcot-Marie-Tooth as a disease model, we aim to clarify the role of mitochondria-ER contact sites in mitophagy and human diseases.

• Project 2. Exploring therapeutic approaches against ageing and mtDNA related diseases: we have developed a Drosophila melanogaster model carrying high number of mtDNA copies containing a deletion of several genes (mtDNA heteroplasmy). Our aim is to use this model to find either genetic or chemical modulators to decrease mtDNA mutation load.

• Project 3. Crossroads in mitochondrial dysfunction pathologies: mitochondrial dysfunction has been related to activation of inflammatory response. We aim to decipher weather inflammation is the cause or the consequence of disease progression and if its modulation can be used as a therapeutic approach against disease progression.