Lysosome-Mitochondrial Crosstalk in Cellular Stress and Disease

The perception of lysosomes and mitochondria as entirely separate and independent entities that degrade material and produce ATP, respectively, has been challenged in recent years as not only more complex roles for both organelles, but also an unanticipated level of interdependence are being uncovered. Coupled lysosome and mitochondrial function and dysfunction involve complex crosstalk between the two organelles which goes beyond mitochondrial quality control and lysosome-mediated clearance of damaged mitochondria through mitophagy. Our understanding of crosstalk between these two essential metabolic organelles has been transformed by major advances in the field of membrane contact sites biology. We now know that membrane contact sites between lysosomes and mitochondria play central roles in inter-organelle communication. This importance of mitochondria–lysosome contacts (MLCs) in cellular homeostasis, evinced by the growing number of diseases that have been associated with their dysregulation, is starting to be appreciated. How MLCs are regulated and how their coordination with other pathways of lysosome–mitochondria crosstalk is achieved are the subjects of ongoing scrutiny, but this review explores the current understanding of the complex crosstalk governing the function of the two organelles and its impact on cellular stress and disease.