Depletion of WFS1 compromises mitochondrial function in hiPSC-derived neuronal models of Wolfram syndrome

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Mitochondrial dysfunction and mitochondria-associated ER membrane (MAM) dysregulation are implicated in neurodegenerative diseases.
• Wolfram syndrome (WS), a rare early-onset neurodegenerative disorder, is linked to the loss of the MAM-resident protein WFS1 and mitochondrial abnormalities.

Purpose of the Study:

• To investigate the role of WFS1 in mitochondrial function in human induced pluripotent stem cell-derived neuronal cells from WS patients.
• To identify molecular interactions involving WFS1 that impact mitochondrial health.
• To explore therapeutic strategies for WS by targeting mitochondrial dysfunction.

Main Methods:

• Utilized human induced pluripotent stem cell-derived neuronal cells from WS patients.
• Investigated the interaction between WFS1 and VDAC1.
• Assessed mitochondrial function, MAMs, and mitochondrial network integrity.
• Evaluated the effects of WFS1 restoration and pharmacological interventions on neuronal viability and bioenergetics.

Main Results:

• Demonstrated mitochondrial dysfunction in WS patient-derived neurons.
• Identified VDAC1 as an interacting partner of WFS1, with loss of interaction in WS cells.
• Showed that restoring WFS1 levels reinstates WFS1-VDAC1 interaction, increases MAMs, and improves the mitochondrial network.
• Confirmed that genetic rescue of WFS1 or pharmacological modulation of mitochondrial function enhances WS neuron viability and bioenergetics.

Conclusions:

• WFS1 plays a crucial role in regulating mitochondrial functionality, potentially through its interaction with VDAC1.
• Dysregulation of the WFS1-VDAC1 interaction contributes to mitochondrial defects in Wolfram syndrome.
• Targeting WFS1-mediated mitochondrial pathways offers a potential therapeutic avenue for WS and other rare diseases characterized by mitochondrial defects.