Disease-causing MFN2 mutants impair mitochondrial fission dynamics by distinct DRP1 dysregulation

Area of Science:

• Cell Biology
• Neuroscience
• Genetics

Background:

• Mitochondrial dynamics, involving fusion and fission, are crucial for cellular health.
• Mitofusins (MFN1, MFN2) regulate mitochondrial fusion, while Dynamin-related protein 1 (DRP1) controls fission.
• MFN2 mutations cause Charcot-Marie-Tooth disease type 2A (CMT2A), but their impact on mitochondrial fission remains unclear.

Purpose of the Study:

• To investigate how MFN2 mutations, associated with CMT2A, influence mitochondrial fission and cellular metabolism beyond their known effects on fusion.
• To analyze the distinct impacts of specific MFN2 mutations (L248H and M376V) on mitochondrial morphology, dynamics, and cellular energetics.

Main Methods:

• Utilized skin fibroblasts from CMT2A patients and engineered mouse cells expressing MFN2 variants.
• Employed live-cell confocal microscopy to assess mitochondrial morphology and dynamics.
• Measured protein levels of fusion/fission machinery, oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and oxidative phosphorylation complex subunits.

Main Results:

• MFN2 mutations impaired mitochondrial fusion and differentially affected mitochondrial fission.
• L248H MFN2 variant led to hyper-elongated mitochondria, impaired fission, and increased OCR.
• M376V MFN2 variant resulted in mitochondrial fragmentation, enhanced fission, and elevated ECAR, correlating with differential Drp1 phosphorylation.

Conclusions:

• MFN2 mutations have distinct consequences on mitochondrial fission and cellular metabolism.
• These findings emphasize the complex interplay between mitochondrial fusion and fission machinery.
• Understanding these differential effects is critical for developing targeted therapies for CMT2A and other mitochondrial disorders.