Every cell in the human body relies on mitochondria to function, but these tiny powerhouses are only as effective as the fatty molecules—lipids—that make up their outer shells. Researchers know that changing a mitochondrion’s lipid composition can reprogram a cell’s identity and behaviour, yet the machinery that controls this lipid delivery remains largely a black box. This project aims to open that box. The team will map the complete set of proteins and mechanisms that shuttle lipids between mitochondria and their partner organelles at specialised contact points. Using CRISPR gene editing, AI-enhanced microscopy, and metabolic tests, they will watch how cells remodel their mitochondrial lipids during nutrient stress and when they differentiate into specialised types. This is fundamental science: it seeks to explain a core biological process that currently has no clear explanation. If successful, it could reveal why lipid-handling goes wrong in a wide range of metabolic and genetic disorders, from diabetes to rare inherited diseases. That knowledge would not yield a treatment tomorrow, but it would give drug developers a precise molecular target to aim at—something they currently lack.
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Mitochondria are dynamic organelles that play an essential role in determining the functions of the cell-types in the human body. Remodelling of the lipid composition of mitochondrial membranes is a key regulator of cellular specialisation. Despite the vital importance in health and disease the mechanisms underpinning these processes remain largely unknown. I propose to systematically investigate the mechanisms that reprogram mitochondrial function through lipids. We will focus on selective lipid transport between organelles at membrane contact sites. I hypothesise that mitochondria interact with specific partner organelles to control the selective import of lipids. The defined mitochondrial lipid composition governs mitochondrial activities and thereby cell function. Using candidate approaches and unbiased ‘omics discovery strategies, we aim at defining the complete machinery around mitochondrial contact-sites and will elucidate how the system remodels the mitochondrial lipid composition during nutrient stress and differentiation. Combining CRISPR-knockout, AI-enhanced imaging and metabolic assays, we will unravel the mechanisms by which cells control and exploit mitochondrial lipid composition to determine cell-fate. Taken together my research programme will open a novel perspective on fundamental cell-biological processes in the regulation of physiological metabolism, which may lead to new treatments of a wide spectrum of metabolic and genetic disorders.
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