Researchers discover a direct pathway for macrophage cleanup

Macrophages are part of the immune system's frontline; they attack and eat invaders to protect surrounding cells. They, along with other cells, maintain intracellular conditions through macroautophagy, using autophagosomes to help digest broken cell components.

The discovery of its molecular mechanism led researcher Dr. Yoshinori Ohsumi to be awarded the Nobel Prize. However, new findings show that internal recycling can take place through a different method entirely, bypassing the macroautophagy process.

In a study published in August 30^th, 2025 in the journal Nature Communications, researchers from The University of Osaka have revealed that macrophages can directly engulf and digest damaged mitochondria and other organelles using a process called microautophagy. Unlike traditional recycling pathways, which can be complex, this shortcut allows lysosome-like compartments inside macrophages to take in broken cell components directly.

Macroautophagy has been extensively studied, but microautophagy is not understood as extensively. We found that this process seems to play a more prominent role than macroautophagy, at least in mitochondria degradation in macrophage due to its lower energy demand."

Shiou-Ling Lu, Study Lead Author and Assistant Professor, The University of Osaka

To do this, the researchers examined lysosome-related organelles, which share traits with lysosomes, membrane-bound organelles that contains enzymes to break down other cells. These lysosome-related organelles were present in macrophages exposed to a mitochondria-damaging chemical.

They found that the damaged mitochondria could be directly engulfed by these lysosome-like organelles, independent of macroautophagy pathways, bypassing the need to digest broken cell components first. Proteins and lipids such as Rab32 GTPase, phosphatidylinositol 3,5-bisphosphates, ubiquitin, and p62/SQSTM1 were found to be crucial for regulating this type of degradation. These proteins and lipids have their own roles in the process, including prompting the beginnings of ubiquitination, and ensuring that certain damaged components are engulfed.

"Our findings reveal that macrophages have an underappreciated way to recycle their own damaged parts, and this process directly shapes how they function," added senior author, Takeshi Noda.

This mitochondrial cleanup is more than housekeeping; by removing damaged mitochondria, macrophages rewire their metabolism toward glycolysis, which fuels a shift into the M1 state: an activated, inflammation-ready mode critical for fighting infection. When researchers knocked out Rab32/38, macrophages lost much of this ability, showing how central microautophagy is to their immune regulation.

This study highlights the diverse and versatile protein degradation systems that work together to coordinate cellular physiology, influencing immune system function. The team suggest that further research would be beneficial for the field, to understand how this process of microautophagy is incorporated into other cellular processes.