Mitochondria and Lysosomes: Discovering Bonds

Abstract

In the last decade, the traditional view of lysosomes has been challenged by the recognition that lysosomes are not only degradative organelles, but also metabolic sensors that play a key role in the regulation of metabolism and cell growth. Similarly, mitochondria are now seen as crucial metabolic hubs dictating cell fate decisions, not just ATP-producing machines. Importantly, these functions are generally performed as a coordinate response of distinct organelles that are physically and functionally connected. While the association between mitochondria and the endoplasmic reticulum is well known, a similar interaction between mitochondria and lysosomes is now emerging. This interaction could be required to shuttle amino acids, lipids and ions such as Ca²⁺ between the two organelles, thereby modulating their metabolic functions. In addition, a tethering complex linking the two organelles has recently been described in yeast, although the mammalian counterpart has yet to be identified. Here, we discuss the implications of these recent findings.

Keywords: Ca2+; TFEB; inter-organelle contact site; lysosome; mitochondria; reactive oxygen species.

Figure 1

Model for the physical and functional interaction between mitochondria and lysosomes. Boxed areas represent outstanding questions: (1) The physical interaction between mitochondria and lysosomes occurs through vCLAMP in yeast but the identity of the proteins mediating this interaction in mammalian cells remain to be determined. (2) Lipid and amino acid metabolism are controlled by both lysosomes and mitochondria. However, how the interaction between the two organelles affects metabolism is still unknown. Possible mechanisms include lipid and amino acid transfer, as well as exchange of ions that regulate mitochondrial function. (3) Ca²⁺ is a key signaling molecule regulated by both lysosomes and mitochondria, in addition to the ER. Ca²⁺ activates several cellular processes including Calcineurin-dependent activation of TFEB and mitochondrial metabolism. As mitochondrial ROS stimulates lysosomal Ca²⁺ release, the role of Ca²⁺ in controlling lysosome-mitochondria cross-talk needs to be addressed. AA, amino acids; ETC, Electron transport chain; ER, Endoplasmic reticulum.