Histone Deacetylase Inhibitors Protect Against Pyruvate Dehydrogenase Dysfunction in Huntington's Disease

Area of Science:

• Neuroscience
• Mitochondrial Biology
• Pharmacology

Background:

• Huntington's disease (HD) is characterized by transcriptional deregulation and mitochondrial dysfunction, including impaired pyruvate dehydrogenase (PDH) activity.
• Histone deacetylase inhibitors (HDACIs) have previously shown potential in ameliorating mitochondrial function in HD models.

Purpose of the Study:

• To investigate the effects of HDACIs on PDH activity regulation in HD models.
• To explore the therapeutic potential of sodium butyrate (SB) in counteracting HD-related mitochondrial and motor deficits.

Main Methods:

• Utilized striatal cells from HD knock-in and YAC128 mice to assess PDH activity and phosphorylation.
• Administered dichloroacetate (PDK inhibitor) and SB (HDACI) to evaluate their impact on mitochondrial function and cell viability.
• Analyzed gene and protein expression of PDH kinases (PDKs) and hypoxia-inducible factor-1 alpha (HIF-1α).
• Assessed motor behavior and coordination in SB-treated YAC128 mice.

Main Results:

• Mutant HD cells showed reduced PDH activity, increased PDH phosphorylation, and elevated PDK1/PDK3 levels.
• SB treatment restored cell viability, mitochondrial metabolism, and PDH activity in mutant cells.
• SB suppressed HIF-1α stabilization, decreased PDK2/PDK3 transcription, and enhanced PDH activation.
• SB treatment ameliorated brain energy levels and improved motor learning and coordination in YAC128 mice.

Conclusions:

• PDH complex is a viable therapeutic target for HD.
• SB effectively counteracts HD-associated mitochondrial dysfunction and motor deficits by enhancing PDH activity.
• SB's neuroprotective effects may involve indirect reduction of PDK expression via HIF-1α inhibition.