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FMRP regulates MFF translation to locally direct mitochondrial fission in neurons

Adam R Fenton1,2,3,4, Ruchao Peng5,6, Charles Bond2,3

  • 1Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Nature Cell Biology
|November 15, 2024
PubMed

Insights

Fragile X messenger ribonucleoprotein (FMRP) regulates mitochondrial fission in neurons by controlling local protein synthesis of mitochondrial fission factor (MFF). This ensures proper mitochondrial health and distribution.

Area of Science:

  • Neurobiology
  • Molecular Cell Biology
  • Genetics

Background:

  • Fragile X messenger ribonucleoprotein (FMRP) is crucial for translation regulation and its dysfunction causes fragile X syndrome.
  • FMRP's role in maintaining mitochondrial homeostasis in neurons is not fully understood.
  • Mitochondrial dynamics, including fission, are essential for neuronal function.

Purpose of the Study:

  • To elucidate the mechanism by which FMRP supports mitochondrial homeostasis in neurons.
  • To investigate the role of FMRP in regulating mitochondrial fission dynamics.
  • To identify the specific molecular targets of FMRP at mitochondria.

Main Methods:

  • Cryo-electron tomography to visualize FMRP granules at mitochondria.
  • Real-time translation imaging to assess local protein synthesis.
  • Analysis of mitochondrial fission dynamics and nucleoid distribution.
  • Investigated the role of endolysosomal vesicles and Rab7 GTP hydrolysis.

Main Results:

  • FMRP granules localize to the mitochondrial midzone, marking fission sites in neuronal axons and dendrites.
  • Mitochondria-associated FMRP granules are ribosome-rich sites for local protein synthesis.
  • FMRP specifically promotes the local translation of mitochondrial fission factor (MFF), regulating fission at the mitochondrial midzone.
  • Disruption of FMRP impairs MFF translation, leading to aberrant fission and mitochondrial nucleoid distribution.

Conclusions:

  • FMRP acts as a key regulator of local MFF translation in neurons.
  • This localized translation enables precise control over mitochondrial fission at the midzone.
  • FMRP-mediated regulation of mitochondrial fission is critical for neuronal health and function.

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