What question did this study set out to answer?

The study investigates MFN2's roles beyond mitochondrial fusion, particularly in preventing protein aggregation and apoptosis in CMT2A.

February 23, 2026Open Access

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

Q: What does this research mean for the field?

MFN2 prevents protein aggregation and mitophagy, providing a protective effect against apoptosis in Charcot–Marie–Tooth type 2A disease. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Key Points

The study investigates MFN2's roles beyond mitochondrial fusion, particularly in preventing protein aggregation and apoptosis in CMT2A.
Examined MFN2's interaction with chaperone HSPA8 and the proteasome
Analyzed the impact of dysfunctional MFN2 in Charcot-Marie-Tooth type 2A models
Assessed mitochondrial and protein quality control mechanisms in cells
MFN2 maintains mitochondrial health by preventing protein aggregation
Loss of MFN2 function leads to increased apoptosis in CMT2A
The interaction of MFN2 with HSPA8 is crucial for proteostasis and cellular health

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.

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

Key Points

Abstract

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