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Physiological autophagy regulation in human disease
One way to deal with damaged cellular components is to destroy them. Autophagy evolved to sustain cells during times of nutrient deprivation. During autophagy, our cells sense, encapsulate and deliver defective components to the lysosome for elimination. Loss of basal macroautophagy in animal models is lethal, and its selective loss from the mouse nervous system leads to pronounced neurodegenerative disease. In a landmark collaborative study, our laboratory recently showed that genetic loss of autophagy in humans leads to neurodegeneration (Collier et al., 2021). Our lab is interested in when, where and why autophagy becomes dysfunctional.
Macroautophagy vs. selective autophagy in aging
Autophagy can be both non-selective (macroautophagy) or selective. Over the past decade, pioneering work from many laboratories has demonstrated that damaged mitochondria can be selectively eliminated using the autophagy machinery, in a process known as "mitophagy". Our lab has been at the forefront of advances in sophisticated genetics and optobiology to visualise mitophagy in mammalian tissues. In contrast to the classical in vitro characterisation of mitophagy as an inducible 'stress response', it has emerged that mitophagy pathways operate constitutively in vivo. Using cutting-edge mouse genetics, neuroscience, and tissue imaging, we recently mapped both mitophagy and macroautophagy across the aging mammalian brain, revealing new insights into these vital pathways.
Metabolic mechanisms of physiological mitophagy
Understanding the mechanistic regulation of mitophagy in vivo is particularly complex and could not be addressed until recently. A major focus of our work is to identify environmental triggers and molecular effectors of PINK1/Parkin-independent physiological mitophagy (McWilliams et al., 2018a, 2018b). How is mitophagy regulated during mammalian tissue development? What are the drivers and effectors of this process in vivo? Why is mitophagy higher in some tissues than in others, and what controls this? We recently discovered a new mitophagy signalling pathway involving a complex interplay between iron levels, lipid droplets and mitochondrial turnover. We want to understand the significance of such organelle crosstalk for mitophagy and other selective autophagy pathways in different contexts.
© 2025 by McWilliams Lab HKI
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