Mitochondrial signaling inhibits autophagosome degradation by regulating lysosomal MCOLN1 channel activity Nuno Raimundo1*, Lorena-Fernandez Mosquera1, King Faisal Yambire1 1IUniversity Medical Center Goettingen, Institute of Cellular Biochemistry, Goettingen, Germany *Corresponding Author (firstname.lastname@example.org)
Mitochondrial signaling following respiratory chain deficiency initially stimulates autophagy in an attempt to promote mitophagy of the affected organelles. However, when the mitochondrial defect persists over time, as in mitochondrial diseases, the autophagy pathway becomes stalled, and autophagosomes accumulate. The mechanisms underlying these effects remain unclear.
Mitochondrial signaling mediated by ROS controls the autophagic flux by regulating the activity of a key lysosomal Ca2+ channel, MCOLN1/TRPML1. The release of Ca2+ to the cytoplasm via MCOLN1 is required for the occurrence of autophagy.
Here, we show that MCOLN1 is activated under acute mitochondrial malfunction, in a AMPK-dependent manner, but shut down under chronic mitochondrial respiratory chain deficiency. The activity of MCOLN1 is regulated by lysosomal PI(3,5)P2, which is synthesized in the lysosomal membrane by the enzyme PIKFYVE. The activity of PIKFYVE is in turn regulated by AMPK. Under chronic mitochondrial malfunction, AMPK signaling decreases, resulting in lower PI(3,5)P2 levels, decreased MCOLN1 activity, and impaired lysosomal degradation, with consequent accumulation of autophagosomes. By directly stimulating the MCOLN1 channel, or by stimulating AMPK signaling in cells with chronic mitochondrial respiratory chain deficiency, we rescue lysosomal function and restore the autophagic flux, in a PIKFYVE-dependent manner.
These results suggest that under acute mitochondrial malfunction the cells promote the removal of damaged mitochondria to restore the network to basal state, but under chronic mitochondrial malfunction the cells inhibit the last steps of autophagy to avoid a complete removal of mitochondria, thus still maintaining essential mitochondrial processes such as Fe-S cluster synthesis.
This project was supported by the European Research Council (Grant 337327).
Credits: None available.
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