The protease Omi regulates mitochondrial biogenesis through the GSK3β/PGC-1α pathway

Area of Science:

• Mitochondrial Biology
• Neuroscience
• Molecular Mechanisms of Disease

Background:

• Loss of Omi protease activity in mnd2 mice causes neurodegeneration and mitochondrial dysfunction.
• The precise mechanisms linking Omi deficiency to neurodegeneration remain unclear.
• Mitochondrial biogenesis is implicated in various neurodegenerative conditions.

Purpose of the Study:

• To elucidate the role of Omi in mitochondrial biogenesis.
• To investigate the Omi-GSK3β-PGC-1α pathway in neurodegeneration.
• To explore therapeutic strategies targeting mitochondrial dysfunction in mnd2 mice.

Main Methods:

• Analysis of mitochondrial components, DNA, and density in mnd2 mice.
• Assessment of Omi's interaction with glycogen synthase kinase 3β (GSK3β) and PPARγ coactivator-1α (PGC-1α).
• Pharmacological inhibition of GSK3β (SB216763) and PGC-1α overexpression in cellular and mouse models.

Main Results:

• Mitochondrial biogenesis is significantly impaired in mnd2 mice.
• Omi cleaves GSK3β, regulating PGC-1α levels; mnd2 mice exhibit increased GSK3β and decreased PGC-1α.
• GSK3β inhibition or PGC-1α overexpression rescues mitochondrial biogenesis and improves motor function in mnd2 mice.

Conclusions:

• Omi is identified as a novel regulator of mitochondrial biogenesis.
• The Omi-GSK3β-PGC-1α pathway is crucial for maintaining mitochondrial health and preventing neurodegeneration.
• Targeting GSK3β represents a potential therapeutic approach for Omi protease-deficient-induced neurodegeneration.