Depression of mitochondrial metabolism by downregulation of cytoplasmic deacetylase, HDAC6

Mitochondria perform multiple functions critical to the maintenance of cellular homeostasis. Here we report that the downregulation of histone deacetylase 6 (HDAC6) causes a reduction in the net activity of mitochondrial enzymes, including respiratory complex II and citrate synthase. HDAC6 deacetylase and ubiquitin-binding activities were both required for recovery of reduced mitochondrial metabolic activity due to the loss of HDAC6. Hsp90, a substrate of HDAC6, localizes to mitochondria and partly mediates the regulation of mitochondrial metabolic activity by HDAC6. Our finding suggests that HDAC6 regulates mitochondrial metabolism and might serve as a cellular homeostasis surveillance factor.

► HDAC6 expression correlates with mitochondrial metabolic activity. ► HDAC6 regulates mitochondrial metabolic activity in the cytoplasm. ► Both deacetylase and ubiquitin binding activities of HDAC6 are linked to it. ► HDAC6 does not affect the expression of nuclear-encoded mitochondrial enzymes. ► Hsp90 partly mediates the regulation of mitochondrial metabolic activity by HDAC6.