Our Discoveries!

• RNA granule-mitochondria contact sites dynamically form in mitochondrial oxidative phosphorylation (OXPHOS) conditions

• Reactive oxygen species (ROS) generated by mitochondrial OXPHOS: 

  • • • promotes TDP-43 localization to cytoplasmic RNA granules, dependent on TDP-43 cysteine oxidation (Cys173/Cys175)

• RNA granule-mitochondria contact sites are regulated via:

  • • • Contact tethering by TDP-43 on RNA granules binding GADD34 on the outer mitochondrial membrane

      • Contact untethering by TDP-43 oxidation at Cys173/Cys175, which releases TDP-43's binding from GADD34

• Crosstalk between TDP-43 and its phosphatase PP1:

  • • • GADD34 is a co-factor for PP1's phosphatase activity to regulate TDP-43's phosphorylation status

      • TDP-43 oxidation regulates the phase separation of PP1 granules

• ALS-associated TDP-43 disease mutant:

  • • • Localizes to the cytoplasm independent of mitochondrial ROS

      • Decreases RNA granule-mitochondria contact tethering duration

      • Promotes condensate formation of PP1 granules lacking TDP-43

• Mitochondria-lysosome contact sites dynamically form in the soma and axons of peripheral neurons

• Disease mutant Rab7 (V162M) linked to the peripheral neuropathy Charcot–Marie–Tooth Type 2B:

  • • • is known to inhibit Rab7 GTP hydrolysis 

      • leads to prolonged mitochondria–lysosome contact site tethering, preferentially in axons of peripheral sensory neurons!

• Charcot–Marie–Tooth Type 2B mutant Rab7 knock-in mouse model have:

  • • • prolonged axonal mitochondria–lysosome contact site tethering

      • defective downstream axonal mitochondrial dynamics due to impaired Rab7 GTP hydrolysis

      • fragmented mitochondria in the axon of the sciatic nerve

      • preferential sensory behavioral abnormalities and neuropathy

*in collaboration with Daniela Menichella & Rob Burgess labs

• Mitochondria-lysosome contacts dynamically form in multiple cell types including neurons

• The network dynamics of mitochondrial and lysosomal populations are modulated by mitochondria-lysosome contacts, including:

  • • • Mitochondrial fission events

      • Inter-mitochondrial contact site untethering events

      • Inter-lysosomal contact site untethering events

• Mitochondria-lysosome contacts regulate various organelle functions, including the transfer of different metabolites, such as:

  • • • Calcium transfer from lysosomes to mitochondria

      • Regulation of amino acid homeostasis

• Defects in mitochondria-lysosome contacts are found in multiple neurodegenerative disorders including:

  • • • Charcot-Marie-Tooth Type 2B disease (Rab7 mutant)

      • Parkinson's disease (GBA mutant)

      • Parkinson's disease (Parkin mutant)

      • Mucolipidosis Type IV (TRPML1 mutant)

• (*Learn more about their mechanistic crosstalk (Leisten et al., 2023) and live microscopy of contacts (Belton et al., 2022).