Pierpaolo Risiglione

Ciclo: XXXIV

Data inizio: 31/10/2018

Curriculum: Biomolecolari

Borsa: UniCT

Titolo tesi: Investigation of mitochondrial function in cell models of neurodegeneration for the development of new therapeutic approaches

Abstract: Mitochondria are indispensable cell organelles which play a central role in bioenergetic metabolism as well as being a crossroad of the apoptotic process for the establishment of cell fate. Maintaining mitochondrial homeostasis is crucial in neurons that relies almost exclusively on this organelle to the general energy supply. In human, neurons are the highest energy demand cell types because of their necessity to sustain activities with high metabolic rate such as neurotransmitter release and restoration of membrane potential. Therefore, even small alterations in proper mitochondrial functioning may result detrimental and could play an important role in the process of aging and in several neurodegenerative diseases including Amyotrophic lateral sclerosis (ALS), Parkinson’s (PD), and Alzheimer’s disease (AD). Although the mitochondrial dysfunction has been widely recognized has a common and shared feature of these disorders, a comprehensive understanding of the underlying mechanisms that lead to the bioenergetic failure of the organelle is still lacking. Accordingly, the aim of this PhD project was to investigate and characterize mitochondrial dysfunction in cellular model of neurodegeneration in order to subsequently test the potential beneficial effect of promising therapeutic molecules. To this purpose, High-resolution respirometry measurements of intact and permeabilized cells, in combination with other biochemical and cellular assays, were conducted. The studies included in this dissertation comprise three main findings: i) a small synthetic peptide derived from the HK1 sequence (NHK1) recovered cell viability and the defective mitochondrial respiratory profile in an ALS cell model; ii) in a toxin-based PD cell model (MPP+ treatment), an expected decrease in complex I activity was detected. In addition, a previously unknown compensatory effect of complex II and an accentuated raise of the dissipative component of respiration were observed; iii) in a genetic PD cell model, the α-Synuclein A53T mutant on one hand increased the dissipative respiration flux not compromising the ATP production, on the other hand it diminished the excess capacity of the mitochondria increasing the organelle’s susceptibility to further stress stimuli. Together with future studies these results may potentially lead to the development of effective therapeutic strategies in order to improve mitochondrial function in patients with neurodegenerative diseases and counteract neurons death.

Tutor: Messina

Data Conseguimento Titolo: 16/12/2021

Linkedin: Indicate il link

Email: pierpaolorisiglione@outlook.it

Periodi all'estero- Sede e data: no (a causa della pandemia)

Esperienze post-Dottorato ed attuale occupazione: Post Doc Fellow (da 02/2022 fino a 12/2022) presso Alzheimer's Center Institute at Temple University (Philadelphia, PA, USA). Research Fellow (da 03/2023) presso MRCPPU at University of Dundee, Scotland (UK).