hyPERTRAce - Tracing the genomic and biochemical regulations of cell fate by the mitochondrial PERmeability TRAnsition pore
Abstract:
Mitochondrial permeability transition (mPT) is a phenomenon that abruptly causes the flux of low-molecular-weight solutes (up to 1500 Da) across the generally impermeable inner mitochondrial membrane. The mPT is mediated by the so-called mitochondrial permeability transition pore (mPTP), a supramolecular entity assembled at the inner and outer mitochondrial membrane interface. The mPT can trigger different cellular responses, from the physiological regulation of metabolism or the production of reactive oxygen species to the activation of apoptosis or necrosis.
The opening of the mPTP has been largely associated with a large spectrum of disorders. For diseases with an acute manifestation (e.g. reperfusion injury) it is believed to drive cell loss via regulated cell death. On the contrary, its involvement in diseases with a chronic manifestation, led to the hypothesis that the mPTP can contribute to cell physiology by regulating the gene expression machinery. Some pieces of evidence have been reported to support this model, although there is no universal consensus on an mPTP-mediated regulation of the transcriptome.
The HyPERTRAce project plans to describe for the first time the relationship between mPTP activity and the regulation of transcription, identifying those genetic, epigenetic and metabolic programs mostly influenced by mPTP activity. To this purpose this proposal brings together two research groups with different but complementary expertise. The HyPERTRAce Principal Investigator has significantly contributed to the molecular definition of the mPTP, identifying the mitochondrial F1/FO ATP synthase as one of the major actors in the formation of the complex. While the co-PI, Calura Enrica, has extensive expertise in omic and multi-omic data analyses and in the application and development of computational methods to dissect cell signaling.
The HyPERTRAce project will generate multiple cellular models to set the mPTP in a sub-toxic open or closed state, to be explored by an integrated panel of omics, biochemical and bioinformatic assays for a hypothesis-free comprehensive characterization of mechanisms impacting the genome regulation. In particular, we will use state-of-art sequencing techniques to assess and probe the mPTP mechanism. The HyPERTRAce project will ultimately result into two major advancements: i) the assessment of a transcriptional signature indicative of the mPTP activity that may be used by research groups from all aboard to screen the involvement of mPTP in a panel of biological conditions using ex-vivo approaches; and ii) it allows the identification of genetic programs activated by the mPTP.
Overall The HyPERTRAce project will allow a better comprehension of the mPTP cell biology and will offer a clear picture of its involvement in disease manifestations.
The opening of the mPTP has been largely associated with a large spectrum of disorders. For diseases with an acute manifestation (e.g. reperfusion injury) it is believed to drive cell loss via regulated cell death. On the contrary, its involvement in diseases with a chronic manifestation, led to the hypothesis that the mPTP can contribute to cell physiology by regulating the gene expression machinery. Some pieces of evidence have been reported to support this model, although there is no universal consensus on an mPTP-mediated regulation of the transcriptome.
The HyPERTRAce project plans to describe for the first time the relationship between mPTP activity and the regulation of transcription, identifying those genetic, epigenetic and metabolic programs mostly influenced by mPTP activity. To this purpose this proposal brings together two research groups with different but complementary expertise. The HyPERTRAce Principal Investigator has significantly contributed to the molecular definition of the mPTP, identifying the mitochondrial F1/FO ATP synthase as one of the major actors in the formation of the complex. While the co-PI, Calura Enrica, has extensive expertise in omic and multi-omic data analyses and in the application and development of computational methods to dissect cell signaling.
The HyPERTRAce project will generate multiple cellular models to set the mPTP in a sub-toxic open or closed state, to be explored by an integrated panel of omics, biochemical and bioinformatic assays for a hypothesis-free comprehensive characterization of mechanisms impacting the genome regulation. In particular, we will use state-of-art sequencing techniques to assess and probe the mPTP mechanism. The HyPERTRAce project will ultimately result into two major advancements: i) the assessment of a transcriptional signature indicative of the mPTP activity that may be used by research groups from all aboard to screen the involvement of mPTP in a panel of biological conditions using ex-vivo approaches; and ii) it allows the identification of genetic programs activated by the mPTP.
Overall The HyPERTRAce project will allow a better comprehension of the mPTP cell biology and will offer a clear picture of its involvement in disease manifestations.
Dettagli progetto:
Referente scientifico: Bonora Massimo
Fonte di finanziamento: Bando PRIN 2022
Data di avvio: 05/10/2023
Data di fine: 05/10/2025
Contributo MUR: 97.901 €
Co-finanziamento UniFe: 32.837€
Partner:
- Università degli Studi di FERRARA (capofila)
- Università degli Studi di PADOVA