Mitofusin MFN2 acts as a molecular sensor preventing protein aggregation and mitophagy, with a protective effect against apoptosis in Charcot–Marie–Tooth type 2A disease

Autophagy Reports, vol. 5, pp. 2629624

Abstract

Mitochondria are central hubs for cellular fitness, empowered by plastic remodeling of their shape, proteome composition, and/or metabolic state. MFN2 (mitofusin 2) mediates mitochondrial fusion and ensures adaptations in response to metabolic changes and stresses. Besides this canonical role, MFN2 serves as a communication hub with other organelles. It tethers mitochondria to the endoplasmic reticulum (ER), lipid droplets, and peroxisomes, regulating calcium buffering, apoptosis, lipid biosynthesis, and lipolysis. Dysfunctional MFN2 causes the hereditary neuropathy Charcot–Marie–Tooth type 2A (CMT2A) and is linked to several metabolic diseases. In a recent publication, we described another fusion-independent role of MFN2 in proteostasis and mitophagy. MFN2 binds the chaperone HSPA8/HSC70 (heat shock protein family A [Hsp70] member 8) and the proteasome, a key function in maintaining mitochondrial and cellular protein quality control, which appears to be lost in the context of CMT2A-associated MFN2 variants.

Authors 4

1. Mariana Joaquim

   University of Cologne

   Affiliation as printed

   University of Cologne

2. Maike Franziska Dohrn Aachen

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   RWTH Aachen University Hospital

3. Arnaud Chevrollier

   Université d'Angers

   Affiliation as printed

   University of Angers

4. Mafalda Escobar‐Henriques corresponding

   University of Cologne

   Affiliation as printed

   University of Cologne