Research Focus
Autophagy: the delivery of damaged components to the
lysosome for destruction
Our cells contain countless components that become defective from disease and the ageing process. One way to deal with damaged cellular components 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
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". Recent advances in mouse genetics and optical reporter systems have made it possible 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. Indeed, different cells within the same organ can exhibit striking heterogeneity. Compared to our understanding of mitophagy in vitro, the regulation of mitophagy in vivo remains an open question.
Suomi & McWilliams (2019)
High-content screening for mitophagy regulators.
Mitochondrial networks in green, engulfed mitochondria in red.
Mitochondrial elimination: a matter of life, disease and death
In addition to generating the chemical energy required for our cells and tissues to survive, mitochondria carry the genetic signature of our maternal lineage, control many diverse cellular functions and are critical to cell viability. Their unique morphology reflects our bacterial past. It is now widely appreciated that mitochondria serve as essential signalling platforms for a variety of molecular reactions within our cells. Despite their static textbook depiction, these membrane-bound organelles form a remarkably dynamic network in our cells. It is not surprising that mitochondrial damage and aberrant mitochondrial metabolism are associated with a diverse array of incurable human diseases. These include neurodegeneration (Parkinson's disease, ALS), ageing, immune dysfunction, certain forms of cancer and inherited mitochondrial disorders. Consequently, our cells have evolved multiple mechanisms to cope with mitochondrial meltdown. We are actively pursuing how mitophagy integrates with other signalling pathways to regulate cell and tissue function and survival during distinct contexts. Our lab has all of the tools and expertise required to go from in vitro mechanistic studies to in vivo pre-clinical analysis using cutting edge reporter and disease models.
Tackling a complex question in tissues: in vivo mitophagy
Understanding the regulation of mitophagy in vivo is particularly complex and could not be addressed until recently. We combine sophisticated mouse genetics and cutting edge approaches in neuroscience, tissue imaging and biochemistry to understand the endogenous regulation of mitophagy pathways in vivo. A primary goal of our research is to both exploit and develop tools to understand mitochondrial homeostasis in health and disease. 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? Is mitophagy altered throughout the ageing process? How does this compare with non-selective macroautophagy in vivo? 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? Can we manipulate autophagy and mitophagy for therapeutic benefit?
These are all questions under active investigation in our laboratory.
Mitophagy in the adult CNS in vivo - A. Rappe
