Periodic Reporting for period 2 - REMIX (Regulation of mitochondrial expression)
Periodo di rendicontazione: 2018-10-01 al 2021-01-31
The main scientific focus of REMIX network was to further understand the molecular mechanism involved in regulation of mitochondrial gene expression that is coordinated by two different genomes. The mitochondrial genome (mtDNA) encodes for key subunits of the oxidative phosphorylation system all RNA components needed for their translation. All other factors needed for mitochondrial DNA replication, DNA repair, transcription and translation are encoded in the nucleus, made in the cytoplasm and then imported into mitochondria. Dysfunction of many different components involved in the regulation of mitochondrial gene expression underlies a great variety of human diseases and modulates organismal aging. To achieve this, REMIX network has recruited 15 highly motivated early stage researchers and over four years of REMIX ITN duration, train them to become the next generation leading scientists in the field. After the recruitment REMIX fellows began a scientific training in their own laboratories, and even more importantly through network-based activities. The extensive network-based training allowed REMIX fellows to form a highly coherent group that communicate on a daily basis sharing their protocols, ideas and successes. This communication is now further perpetuated by REMIX fellows themselves and resulted in a couple of very nice and collaborative publications. This strong and lasting connection between REMIX fellows is obviously an added value of the whole REMIX consortium. Scientific achievements and results obtained by REMIX fellows are no less impressive as they identified novel players and pathways involved in different steps of mitochondrial gene expression.
REMIX recruited 15 highly motivated ESRs in order to train them to become the next generation leading scientists in the field of mitochondrial research. REMIX fellows began a scientific training in their own groups, and more importantly through network-based activities. Fellows attended 5 courses in transferable skills timely planned to follow scientific progress of ESRs including: (1) Statistical Literacy, (2) Scientific Writing, (3) Data analysis, (4) Data Visualisation, (5) Proposal Writing. Besides, fellows attended specialized workshops like: (1) Mass Spectrometry (2) Drug Development, (3) EMBO Workshop on Molecular Biology of Mitochondrial gene Expression, (4) EMBO/FEBS Advance Course on Mitochondrial in life, death and diseases, (5) Remix RNA School. The most important training was through the research they’ve conducted and accomplished through the three REMIX research WPs: (i) Novel insights into maintenance of mitochondrial genome, (ii) Molecular mechanisms of mitochondrial transcription and (iii) RNA processing and Identification of novel factor governing mitochondrial ribosomal assembly and protein synthesis. Within REMIX, we developed a number of novel models for mitochondrial dysfunction that allowed us to further examine the in vivo role of many proteins involved directly or indirectly in mitochondrial gene expression. We also modeled in mice some of the most common patient mutations found in mitochondrial diseases. Combining the in vivo approaches with sophisticated biochemical methodology, in a collaborative effort (MRC-UCAM), together with (UGOT) and (UCO), provided evidence that explain the detailed molecular mechanism leading to mtDNA deletions and depletion in the most common mutations of mtDNA polymerase gamma (POLG). Similarly, (UGOT) together with (UNEW) and (UCO) focused on understanding the role of mitochondrial matrix protease LONP1 in the regulation of mammalian mitochondrial gene expression. They managed to crystalize the human LONP1 with its substrate TFAM, and also work on development of drugs targeting LONP1 function. These collaborative projects would not be possible without REMIX. Fellows actively attended international scientific conferences where they presented their results. Unfortunately, during 2020 this abruptly stopped due to force major – covid 19 pandemic that resulted in majority of international conferences being postponed. Nevertheless, we hope, our fellows will be able to publish and present their scientific achievements in front of larger audience in near future. REMIX website aimed to address different audiences but also enabled communication within Consortium. The website contains a section dedicated to communication and dissemination of results where fellows posted their experiences in the form of blogs. To maximize dissemination of results and public engagement, active social media dissemination started from Month 18 through 3 channels, where all 15 fellows post pro-actively. The sites remain active and still used by the fellows. Direct outreach aimed toward general public, elementary and high school students, as a part of e.g. European Researcher’s Night or Light up for Mito: Global Mitochondrial Disease Awareness Week.
The overall objective of REMIX was to shed more light on the molecular mechanism regulating mitochondrial gene expression on all different levels, from mtDNA replication, to transcription and translation, but also crosstalk between nuclear and mitochondrial genomes essential for proper function of energy generating system – OXPHOS. Despite encoding only 13 polypeptides, mitochondrial gene expression is in the heart of cellular energy production and defects in the synthesis, import, and modification of mitochondrial polypeptides as well as defective assembly of multi-subunit OXPHOS complexes result in devastating diseases that primarily affect tissues with a high metabolic demand, such as the nervous, muscular, cardiac, ocular and endocrine systems. These heterogeneous diseases are very prevalent and affect children and adults alike. REMIX aimed to understanding the mechanisms governing the mitochondrial gene expression and thus its associated pathologies. We wanted to understand the regulation of these processes in response to changing metabolic demands and discover mechanisms governing crosstalk between the two genomes needed for the coordination of OXPHOS assembly and maintenance. The multidisciplinary nature and technical complexity of the proposed work made it too large in scope for any individual research group, and therefore REMIX was established to coordinate and integrate European mitochondrial gene expression research and more importantly, to train the next generation of scientists in the field of mitochondrial biology. Our multidisciplinary team, which harnesses the different expertise (genetics, molecular and cell biology, biochemistry and structural biology) of researchers across Europe, was perfectly tailored to answer these questions and preliminary results included in this periodic report clearly show this. Fifteen brilliant ESRs that joined our teams were trained in the broad range of skills and expertise in mitochondrial biology, biochemistry and genetic and also complementary soft skills. They were the driving force behind REMIX goals that resulted not only in great scientific discoveries, but also their personal development into the independent young scientists with great perspective to become future leaders in the field. With our ESRs working on their individual projects, but also by pooling resources, stimulating researcher exchange and training-promoting knowledge transfer, and enhancing scientific communication between researchers with complementary expertise, we achieved REMIX goals.