Scientists found a cholesterol switch that controls the lysosome's ability to digest damaged mitochondria
Scientists found a cholesterol switch that controls the lysosome's ability to digest damaged mitochondria
On 16 September, Nature Communications published a paper from the laboratory of Yasunori Saheki (Nanyang Technological University, Singapore) describing how cells direct cholesterol to the lysosomal membrane precisely when damaged mitochondria are being digested. The authors showed that this cholesterol influx is triggered by a specific protein relay and is required for the lysosome to maintain its acidity, membrane integrity, and the completion of digestion.
Every cell continuously culls its mitochondria, the organelles that generate ATP. A damaged mitochondrion is wrapped in a membrane vesicle and delivered to the lysosome, an acidic digestive compartment that breaks down cellular waste and recycles its components. The worse the lysosome performs this job, the more damaged mitochondria accumulate inside the cell, and that accumulation is one of the hallmarks of cellular aging.
Saheki and colleagues traced where the lysosome obtains cholesterol during clearance of damaged mitochondria, since its membrane normally carries very little. They found that the enzyme PI4KIIα marks the lysosomal membrane with a specific lipid tag. That tag activates the transporter protein OSBP, which shuttles cholesterol directly from the endoplasmic reticulum, the intracellular factory where the cell produces and stores lipids. The damaged mitochondrion itself could theoretically serve as a source, but its membranes contain too little cholesterol.
The outflow of cholesterol from the ER activates the protein SREBP-2, which triggers synthesis of new cholesterol: the cell simultaneously supplies the lysosome and replenishes the factory's own reserves. This feedback loop was anticipated by earlier work from the same laboratory, where hyperactivation of OSBP had already been shown to lower ER cholesterol and activate SREBP-2.
When the authors pharmacologically depleted cellular cholesterol, the lysosome digested damaged mitochondria markedly less efficiently, lost acidity, and its membrane became more vulnerable to damage. All three effects reversed once cholesterol was restored. This means that cholesterol influx is a necessary condition: the lysosome completes digestion only as long as enough cholesterol is present on its membrane.
The fatty acids released during this digestion also have a defined downstream fate: the enzyme DGAT1 converts them into neutral fat and packages them into new lipid droplets. The cell thus recycles mitochondrial debris into a safe storage form, preventing free fatty acids from becoming toxic to the cytoplasm.
This pathway is engaged specifically during clearance of damaged mitochondria. The same cholesterol accumulation appeared when the authors damaged mitochondria by a different method (iron depletion), while ordinary starvation without mitochondrial targeting did not produce the accumulation. This indicates a targeted cellular response to mitochondrial damage specifically.
The authors draw a direct connection to neurodegeneration: in people carrying mutations in PINK1 and Parkin, the genes responsible for routing mitochondria to the lysosome, a hereditary form of Parkinson's disease develops. Lysosomal dysfunction is also observed in Alzheimer's disease, where a risk score based on 14 lysosomal pathway variants correlated with lysosomal damage in the brain. The authors performed all experiments in cultured skin cells and other cell lines; their link to these diseases is drawn from independent literature on lysosomal dysfunction in neurodegeneration.
Each link in the chain (enzyme, transporter, regulatory protein) was individually knocked out by the authors, after which cholesterol was restored to the cell: the effect recovered each time. This is how the authors established the causal role of every link in the chain.