Microautophagy is essential for preventing aging, lysosome study finds

To age or not to age? How does aging affect organisms at the cellular level? What mechanisms help cells survive self-inflicted or external damage? Lysosomes – critically important cellular structures – are known to be essential for digesting damaged cellular components and pathogens, as well as maintaining stability within cells and tissues. But can they also be repaired, and if so, how?

In a study published this month in EMBO ReportsResearchers from Osaka University and Nara Medical University have shown that damaged lysosomes are repaired by a mechanism called microautophagy and identified two key regulators of this process.

Microautophagy is one of the three main types of autophagy in most higher organisms. It is a regulated process by which cellular components that have become dysfunctional or no longer needed are broken down. Although it is thought to be involved in defense mechanisms collectively called lysosomal damage responses, the details remain unknown.

Lysosomes are frequently damaged and lysosomal dysfunction has been associated with accelerated aging and shortened lifespan. In this study, the researchers attempted to understand the repair mechanisms. To identify a new regulator of the lysosomal damage response, they focused on a signaling pathway called the Hippo pathway, which controls several processes such as cell growth.

They destroyed individual components of the Hippo pathway in human cells, then observed whether the cells could respond to the induced lysosomal damage. This screen revealed that a protein called serine-threonine kinase 38 (STK38) is essential for the lysosomal damage response.

They then discovered that STK38 works with a protein complex called endosomal sorting complex required for transport machinery (ESCRT), which was already known to be linked to lysosomal repair.

“STK38 recruits vacuolar sorting protein 4 (VPS4) to damaged lysosomes and is crucial for the disassembly of the ESCRT machinery at the end of the repair process,” explains the study’s lead author, Monami Ogura. The team further discovered that lysosomal membrane repair by the ESCRT machinery is mediated by microautophagy.

Additionally, they identified that non-canonical lipidation of a subfamily of autophagy-related protein 8 (ATG8) molecules – the key autophagy proteins – known as autophagy receptor-associated proteins Gamma-aminobutyric acid (GABARAP) is necessary for this process. Lipidation, the process of modifying ATG8 with lipid extensions, is the main process involved in autophagy. In noncanonical lipidation, ATG8s are lipidated into single-membrane endolysosomes, instead of the double-membrane phagophores observed in canonical lipidation.

Researchers have shown that GABARAPs are essential in the first step of the lysosomal repair process.

“We showed that non-canonical ATG8 lipidation is crucial for the initial recruitment of the ESCRT machinery to damaged lysosomes and their subsequent repair,” explains lead author Shuhei Nakamura.

The team also showed that depletion of microautophagy regulators increased the rate of senescent cells and shortened lifespan in C. elegans. STK38 and GABARAP also have evolutionarily conserved roles, indicating the importance of this pathway in maintaining lysosomal integrity, healthy cellular function, and preventing cellular senescence and organismal aging. The detailed understanding provided by this study paves the way for healthy aging and has great therapeutic value for the treatment of age-related diseases.