Autophagic lysosome reformation in health and disease

Abstract

Lysosomes are the primary degradative compartment within cells and there have been significant advances over the past decade toward understanding how lysosome homeostasis is maintained. Lysosome repopulation ensures sustained autophagy function, a fundamental process that protects against disease. During macroautophagy/autophagy, cellular debris is sequestered into phagophores that mature into autophagosomes, which then fuse with lysosomes to generate autolysosomes in which contents are degraded. Autophagy cannot proceed without the sufficient generation of lysosomes, and this can be achieved via their de novo biogenesis. Alternatively, during autophagic lysosome reformation (ALR), lysosomes are generated via the recycling of autolysosome membranes. During this process, autolysosomes undergo significant membrane remodeling and scission to generate membrane fragments, that mature into functional lysosomes. By utilizing membranes already formed during autophagy, this facilitates an efficient pathway for re-deriving lysosomes, particularly under conditions of prolonged autophagic flux. ALR dysfunction is emerging as an important disease mechanism including for neurodegenerative disorders such as hereditary spastic paraplegia and Parkinson disease, neuropathies including Charcot-Marie-Tooth disease, lysosome storage disorders, muscular dystrophy, metabolic syndrome, and inflammatory and liver disorders. Here, we provide a comprehensive review of ALR, including an overview of its dynamic spatiotemporal regulation by MTOR and phosphoinositides, and the role ALR dysfunction plays in many diseases.

Autophagy and neurodegeneration: Unraveling the role of C9ORF72 in the regulation of autophagy and its relationship to ALS-FTD pathology

“…In addition to negatively regulating autophagy and preventing its overactivation, mTORC1 reactivation aids in the regeneration of lysosomes from autolysosomes ( Figure 1 ). When this process, known as ALR, is compromised, the cells become far more vulnerable to starvation-induced cell death ( Chen X. et al, 2021 ; Nanayakkara et al, 2022 ). Among all the different cells of our body, neurons are particularly vulnerable to compromised ALR, which predominantly impacts correct neuronal functioning.…”

“…Among all the different cells of our body, neurons are particularly vulnerable to compromised ALR, which predominantly impacts correct neuronal functioning. Unsurprisingly, ALR impairment is linked to an ever-increasing number of diseases, and classified as a subgroup of lysosomal disorders, involving an imbalance in lysosome homeostasis, leading to autophagy inhibition ( Nanayakkara et al, 2022 ). Mutations in different genes, such as spastizin and spatacsin are associated with autosomal recessive hereditary spastic paraplegia.…”

Crosstalk between Autophagy and RLR Signaling

“…When the autophagy process is completed, the reactivation of mTOR by nutrient recycling subsequently terminates autophagy by coordinately suppressing the initiation of autophagy and activating autophagic lysosome reformation (ALR) [ 205 ]. Several molecules, including phospholipid PtdIns(4,5)P(2), the functional molecules involved in endocytosis, clathrin, and motor movement, kinesin, the lysosomal efflux permease, and the ubiquitin E3 ligase Cullin 3-Kelch-like protein 20 (KLHL20), have been shown to participate in ALR activation at the termination stage of autophagy [ 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 ].…”

Lysosomal dysfunction in diabetic cardiomyopathy

“…Depending on the degree of the LMP, there are two types of responses that repair damaged lysosomes (Figure 1B): 1) Restoring limited membrane rupture, including endosomal sorting complex required for transport (ESCRT) machinery (Niekamp et al, 2022;Olmos, 2022), sphingomyelin scrambling (Niekamp et al, 2022), and phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway (Tan and Finkel, 2022); 2) Regenerating entire vesicles through autophagy (lysophagy and autophagy lysosome reformation ALR). (Nanayakkara et al, 2022).…”

“…In ALR, the autolysosome membrane is extruded along microtubules to generate membrane tubes called "reformation tubules." The tubes are fragmented into "proto-lysosomes" and mature into functional lysosomes (Nanayakkara et al, 2022). As long as lysosomes can contain the degree of stress that damages themselves, the cellular responses strive to maintain cellular homeostasis.…”