Mitochondrial dysfunction associated to permeability transition pore phenomenon in lung inflammation controls mitochondria-derived vesicles biogenesis and release in cystic fibrosis

Although Cystic Fibrosis (CF) is considered a rare disorder, it is the most common lethal inherited disease in Caucasians worldwide. In recent decades, significant advances have been obtained in understanding the basic CF defect and in developing new therapies, termed “CFTR modulators”, which act on mutated protein to rescue in part its defective function(1). Despite these exciting therapeutic improvements, different questions remain unanswered on CF lung pathology. Increasing evidence supports the idea that the exacerbation of pulmonary inflammation in CF lung depends also on altered crosstalk between airway and immune cells. Nonetheless, this intercellular communication is still widely obscure; therefore, innovative concepts and approaches are desperately needed to uncover this aspect of CF lung pathology, emerging as a new target for the development of more effective anti-inflammatory treatments. Currently, it is well documented that in addition to traditional endocrine and paracrine communication, the cells converse via extracellular vesicles (EVs) under physio-pathological conditions(2). EVs cargo includes plasma membrane and endosomal proteins, but EVs also contain material from other cellular compartments, including mitochondria. Recent evidence suggests that mitochondria-derived vesicles (MDVs) may be transferred and that mitochondrial content may alter the metabolic and inflammatory response of recipient cells(3–5). MDVs levels and cargo may be altered when mitochondrial dysfunction occurs, indicating that MDVs biogenesis and release are conditioned by onset of several pathological conditions where mitochondrial physiology is compromised, such as in CF. This could have important implications for CF pathological progression and treatment.
Mitochondrial dysfunction affects the subset of mitochondrial constituents altering their levels and cargo. These pathophysiological processes could be supported by the mitochondrial permeability transition pore (mtPTP) phenomenon triggered by impaired bioenergetics. We will evaluate the pharmacological and genetically mtPTP modulations to understand the MDVs bioegenesis and release in healthy and CF airway cell models. To understand the molecular mechanism of MDVs effect and formation connecting the mitochondrial homeostasis will be considered the proteomic profile of MDVs and evaluate their bioenergetic structure and mitochondrial parameters. Finally, recipient immune cells obtained from donor and CF patients will be analyzed and validated for the impact of MDVs as immune modulators and their effect on the mitochondria-related process and activities of recipient immune cells.
On balance, the mitochondrial processes linking MDVs biology and mitochondrial dynamics in CF lung disease will be considered to test new and alternative therapeutic strategies.