Elevated mitochondrial metabolism in Down syndrome iPSCs reduces commitment to neuroectoderm

Area of Science:

• Neuroscience
• Developmental Biology
• Cell Biology

Background:

• Down syndrome (DS) is characterized by impaired neurogenesis.
• Mitochondrial dysfunction is implicated in various neurodevelopmental disorders.

Purpose of the Study:

• To investigate the role of mitochondrial metabolism in neurogenesis deficits in DS.
• To explore potential therapeutic targets for improving neurodevelopment in DS.

Main Methods:

• Utilized induced pluripotent stem cells (iPSCs) from individuals with DS (3S-iPSCs) and isogenic controls.
• Assessed mitochondrial membrane potential, calcium uptake via the mitochondrial calcium uniporter (MCU), cell cycle progression, and primary cilia growth.
• Investigated the effects of MCU inhibition and proliferation slowing on neuroectoderm commitment.

Main Results:

• DS-derived iPSCs exhibit heightened mitochondrial membrane potential and calcium uptake capacity.
• Accelerated cell cycle progression in 3S-iPSCs leads to reduced primary cilia formation.
• Inhibition of MCU or slowed proliferation restored ciliation and enhanced neuroectoderm commitment.

Conclusions:

• Increased mitochondrial metabolism in DS stem cells dysregulates a mitochondria-to-cilia signaling axis crucial for early neurogenesis.
• This pathway is a potential target for therapeutic interventions to improve neurodevelopment in Down syndrome.