Selective Autophagy of Mitochondria on a Ubiquitin-Endoplasmic-Reticulum Platform

Area of Science:

• Cell Biology
• Molecular Biology
• Autophagy Research

Background:

• The precise mechanisms and coordination of autophagy machinery and selective receptors during mitophagy remain unclear.
• It is unknown whether mitophagy relies on pre-existing membranes or is initiated on damaged mitochondria surfaces.

Purpose of the Study:

• To elucidate the dynamics and coordination of autophagy machinery and selective receptors in mitophagy.
• To determine if mitophagy is dependent on pre-existing membranes or triggered on damaged mitochondrial surfaces.

Main Methods:

• Utilized genetic and advanced imaging experiments.
• Employed ivermectin, a ubiquitin-dependent mitophagy inducer.
• Investigated the roles of key autophagy proteins (TBK1, FIP200, ATG13, ULK1/2), receptors, and the VPS34 complex.

Main Results:

• Earliest step identified: ubiquitination of mitochondrial fragments, followed by TBK1 auto-phosphorylation.
• FIP200 and ATG13 act at distinct stages; ULK1/2 are dispensable. Receptors function upstream of ATG13 but downstream of FIP200.
• VPS34 complex acts at the omegasome stage. Mitochondria are ubiquitinated and dynamically encased by endoplasmic reticulum (ER) strands, forming platforms for mitophagosome assembly.

Conclusions:

• Mitophagy initiation involves ubiquitination of damaged mitochondria and dynamic ER strand encasement, independent of functional autophagy machinery or adaptors.
• The findings propose a novel model for mitophagosome formation on ubiquitinated mitochondrial platforms cradled by ER.