Lysosome-Mitochondrial Crosstalk in Cellular Stress and Disease

Abstract

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.

Keywords: crosstalk; lysosomes; membrane contact sites; mitochondria.

Figure 1

Electron micrograph of a mitochondria:lysosome contact (MLC). A lysosome (false-colored magenta) and mitochondria (false-colored green) are shown forming extended MLCs in fibroblasts from an NPC patient lacking functional NPC1. Scale bar, 250 nm.

Figure 2

Coupled dysfunction of lysosomes and mitochondria in Niemann–Pick type C (NPC) disease, leading to increased ROS production and innate inflammation. Illustration of crosstalk between lysosomal and mitochondrial dysfunction in NPC. A defective NPC1 resulting in the accumulation of lysosomal cholesterol and sphingolipids is also associated with reduced acid ceramidase activity and increased expression of the mitochondrial cholesterol import protein STARD1. STARD3 on LE/lysosomes and mitochondrial Tom40, TSPO, and StARD1 have been implicated in mitochondrial cholesterol (mChol) accumulation [15]. Increased mChol disrupts membrane fluidity and impairs electron transport chain (ETC) complexes, leading to elevated mitochondrial reactive oxygen species (mtROS) production and reduced oxidative phosphorylation (OXPHOS). Consequences include decreased mitochondrial membrane potential (Δψm) and ATP synthesis. In parallel, mitochondrial glutathione (mGSH) depletion through reduced 2-oxoglutarate carrier (2-OGC) activity due to a change in membrane fluidity exacerbates oxidative damage [99,108,109]. Increased mtROS activates innate inflammatory pathways including cGAS/STING signaling, and dysfunctional NPC1 is unable to recruit STING to the lysosome for degradation, further increasing the inflammatory response. This cross-organelle dysfunction highlights a critical axis driving cellular damage and inflammation in NPC pathology. The solid arrows represent direct transport or transfer processes, while the dashed arrows indicate proposed effects or signaling pathways, such as the proposed route of STARD3 mediated cholesterol transfer [15]. The red arrows highlight pathological outcomes in NPC, such as decreased mitochondrial membrane potential (Δψm) and the crossed-out arrow represents inhibited reduction of mitochondrial reactive oxygen pieces due to decrease in mGSH transport. Image created with BioRender.com (accessed on 24 November 2024).

Figure 3

Lattice structured illumination microscopy data showing mitochondrial fission sites contacted by LE/lys in ARPE19. Live cell images generated using the Zeiss Lattice SIM 3 in ARPE19, with the mitochondrial marker PKmito ORANGE (magenta) and cells transiently transfected with the LE/lysosomal marker STARD3-GFP (green). Time-stamped images of the contact formation, mitochondrial fission, and subsequent untethering of the membrane contact site between mitochondria and LE/lysosomes. White arrows represent MCSs.