Super-Resolution deciphers DRP1's Cut: Mitochondrial Fission during Apoptosis via SMLM and MINFLUX

Descrizione del progetto

Svelare i meccanismi di DRP1 nella fissione mitocondriale durante l’apoptosi

I mitocondri, ovvero le centrali elettriche delle nostre cellule, devono dividersi e fondersi in un processo equilibrato per mantenerle in condizioni di salute; quando questo equilibrio viene alterato, possono insorgere malattie come il cancro o la neurodegenerazione. Durante la morte cellulare, un processo essenziale per la vita, la divisione mitocondriale (fissione) si intensifica e la proteina chiave della fissione DRP1 interagisce con le proteine della BAX e BAK, associate a tale morte delle cellule; ciononostante, le esatte modalità con cui ciò avviene su scala molecolare sono tuttora poco chiare. Supportato dal programma di azioni Marie Skłodowska-Curie, il progetto SuperCut utilizzerà la microscopia avanzata a super risoluzione per studiare la proteina DRP1 durante la fissione mitocondriale nelle cellule morenti: la microscopia per la localizzazione di singole molecole ne rivelerà la nanostruttura, mentre il tracciamento MINFLUX ne catturerà il comportamento dinamico, generando una comprensione che potrebbe orientare nuove terapie rivolte alla fissione mitocondriale disfunzionale.

Obiettivo

Illnesses such as neurodegenerative diseases and cancer represent significant public health challenges due to their increasing prevalence, mortality rates, and societal impact. Mitochondrial dysfunction, specifically the dysregulation of mitochondrial fission, is implicated in these diseases.
Together with mitochondrial fusion, the mitochondrial fission process, or the division of mitochondria, is essential for maintaining cellular health. The effector protein of mitochondrial fission is the dynamin-related protein 1 (DRP1). During cell death, mitochondrial fission is elevated and DRP1 interacts with the key apoptotic proteins BAX and BAK. However, the precise role, regulation, and positioning of DRP1 in mitochondrial fission, especially with regards to BAX and BAK during apoptosis remain unclear.
The project SuperCut will unravel the molecular architecture of DRP1 as well as its motion pattern during mitochondrial fission in the context of apoptosis by using advanced super-resolution microscopy techniques. Single-molecule localization microscopy (SMLM) will enable the visualization of the spatial organization of DRP1 and its relation to apoptotic pore formed by BAX and BAK. MINFLUX tracking will provide insights into the spatial dynamics of DRP1 and its adaptors in healthy cells and their interaction with BAX and BAK in apoptotic cells. By elucidating these mechanisms, the project will open new avenues for innovative therapeutic strategies targeting dysfunctional mitochondrial fission.
The research for SuperCut will be conducted by me, Dr. Sarah Schweighofer at the Max Perutz Laboratories under the supervision of Prof. Jonas Ries, leveraging cutting-edge microscopy techniques to push the boundaries of our understanding of mitochondrial dynamics in health and disease. This deepening of my super-resolution microscopy expertise will enable me to become an independent multidisciplinary scientist with high impact in the life sciences.