The review paper here provides an interesting perspective on the interaction between mitochondria and lysosomes, looking at the mechanics of their membrane contact sites in the context of mitochondrial quality control and its age-related decline. Every cell plays host to hundreds of mitochondria, bacteria-like organelles responsible for generating adenosine triphosphate molecules to power cellular processes. Mitochondrial function declines throughout the body with age, and this appears to be largely a problem of failing quality control. The quality control processes of mitophagy identify worn and damaged mitochondria, ensuring that they are transported to a lysosome to be dismantled by enzymes. As mitophagy falters, cells become host to ever more malfunctioning or poorly functioning mitochondria, and this has profound negative effects on tissue function, particularly in energy-hungry organs such as the brain and heart.
Mitochondrial dysfunction has attracted considerable interest as a target for geroprotective interventions. Indeed, mitochondria play varied roles in a multitude of biological processes, including integration of cell death signaling and preservation of cell stemness. Albeit long considered to be standalone organelles, a great deal of evidence indicates that mitochondria interact physically and functionally with other cellular compartments via membrane contact sites and tethering molecules. In particular, mitochondria establish connections with the endosomal compartment and lysosomes. These interactions support cytosolic shuttle systems of ions and metabolites across organelles, and participate to the regulation of cellular housekeeping processes.
The mitochondrial-lysosomal axis is a major actor in mitochondrial quality control (MQC), a hierarchical network of pathways that ensure organellar homeostasis through the coordination of mitochondrial proteostasis, dynamics, biogenesis, and autophagy. While continuous cycles of fusion and fission preserve mitochondrial shape and dilute damage along the network mitochondrial hyper-fission segregates damaged or unnecessary organelles from the network. Severely damaged mitochondria are subsequently disposed via a selective form of autophagy referred to as mitophagy. Cleared mitochondria are eventually replenished via biogenesis to maintain an adequate mitochondrial pool within the cell.
Dysregulation of mitophagy and disruption of the mitochondrial-lysosomal axis coupled with abnormal EV secretion have been implicated as mechanisms in the aging process and related disease conditions. More specifically, the garbage theory of aging poses that damaged mitochondria, protein aggregates, and lipofuscin accumulate as a result of inefficient cellular quality control. The progressive accrual of intracellular “waste” further depresses cell recycling processes, thereby impinging on cell homeostasis and tissue integrity.
Functional connections between lysosomes and mitochondria have been described. Indeed, defects in either of the two organelles induce impairments in the other, indicating the existence of a mitochondrial-lysosomal axis. The genetic ablation of mitochondrial transcription factor A (TFAM), responsible for mitochondrial DNA replication, transcription, and maintenance, increases the number of lysosomes in T cells. However, lysosomal activity is impaired when deficient mitochondrial respiration and disruption of endolysosomal trafficking occur, suggesting a link between primary mitochondrial dysfunction and lysosomal storage disorders. Moreover, the restoration of lysosomal pH by lysosome-targeted nanoparticles reinstates mitophagy in pancreatic cells exposed to high concentrations of free fatty acids. These findings indicate that, at least under lipotoxic conditions, mitochondrial dysfunction develops downstream of lysosomal alkalization and that recovery of lysosomal acidity restores MQC.
Mitochondrial dysfunction, arising from failure of mitochondrial fidelity pathways, is a major mechanism driving aging and the development of age-related diseases. In this context, MQC processes may represent ideal targets for geroprotective interventions. Notably, many of the proteins involved in MQC pathways have been localized at inter-organelle interface. Such contact sites may therefore participate to some of the processes responsible for cell dyshomeostasis triggered by mitochondrial dysfunction. Hence, a deeper characterization of the structures ensuring inter – organelle crosstalk is crucial for a comprehensive assessment of mitochondrial dysfunction during aging. This knowledge, in turn, is necessary to unveil strategic pathways that may be targeted for geroprotective interventions.