HDAC6 preserves BNIP3 expression and mitochondrial integrity by deacetylating p53 at lysine 320

Area of Science:

• Cellular Biology
• Neuroscience
• Biochemistry

Background:

• Histone deacetylase 6 (HDAC6) deacetylates p53 at multiple sites, influencing apoptosis and tumor suppression.
• Previous work showed p53 acetylation at K320 increases in HDAC6-ablated mouse liver.
• The biological impact of p53 K320 acetylation remains unclear.

Purpose of the Study:

• To investigate the role of HDAC6 deacetylase activity in regulating p53 K320 acetylation.
• To elucidate the biological consequences of p53 K320 acetylation, particularly in the brain.
• To determine the link between HDAC6, p53 acetylation, mitophagy, and mitochondrial integrity.

Main Methods:

• Utilized HDAC6 knockout mouse models and MEFs (mouse embryonic fibroblasts).
• Assessed p53 acetylation at K320 and BNIP3 expression levels via Western blotting and other biochemical assays.
• Employed a K320R mutant p53 to mimic deacetylation and observed its effect on BNIP3 expression.
• Examined mitochondrial morphology in neurons from HDAC6 knockout mice.

Main Results:

• HDAC6 knockout mouse brains showed significantly higher p53 K320 acetylation compared to other tissues.
• p53 K320 acetylation levels were inversely correlated with BNIP3 expression.
• Restoration of BNIP3 expression was observed upon overexpression of K320R mutant p53 in HDAC6 knockout MEFs.
• Neurons lacking HDAC6 exhibited reduced BNIP3 expression and accumulated abnormal mitochondria with swollen cristae.

Conclusions:

• HDAC6 deacetylase activity is critical for regulating p53 acetylation at the K320 site.
• HDAC6-mediated deacetylation of p53 at K320 is essential for maintaining BNIP3 expression.
• This pathway is crucial for mitophagy and preserving mitochondrial structural integrity, with neurons being particularly vulnerable to HDAC6 loss.