The deleterious duo of neurodegeneration: Lysosomes and mitochondria

Many studies have demonstrated that the accumulation of aggregateprone proteins due to defects in cellular quality control systems contributes to the development of neurodegenerative diseases. One form of quality control within neurons is autophagy, an intracellular pathway involved in the breakdown of cytosolic constituents. Lysosomes mediate autophagy, and their dysfunction may contribute to perturbations in cellular homeostasis and affect other organelles such as mitochondria. Mitochondrial malfunction may then further perpetuate lysosomal damage and initiate inflammatory responses. Therefore, lysosomes and mitochondria share a reciprocal relationship where dysfunction in one often affects the function of the other. These consequences of lysosome and mitochondrial impairment complete a deleterious feedback loop that concludes not only in neurodegeneration but also neuroinflammation. Herein, we discuss the primary types of autophagy and their underlying mechanisms, the regulation of lysosomal biogenesis and function, and the link between lysosomal and mitochondrial dysfunction. We conclude this chapter by assessing the role of lysosomal dysfunction in neurodegenerative diseases.