Activation of Class I histone deacetylases contributes to mitochondrial dysfunction in cardiomyocytes with altered complex activities

ABSTRACT

Histone deacetylases (HDACs) play vital roles in the pathophysiology of heart failure, which is associated with mitochondrial dysfunction. Tumor necrosis factor-α (TNF-α) contributes to the genesis of heart failure and impairs mitochondria. This study evaluated the role of HDACs in TNF-α-induced mitochondrial dysfunction and investigated their therapeutic potential and underlying mechanisms. We measured mitochondrial oxygen consumption rate (OCR) and ATP production using Seahorse XF24 extracellular flux analyzer and bioluminescent assay in control and TNF-α (10 ng/ml, 24 h)-treated HL-1 cells with or without HDAC inhibition. TNF-α increased Class I and II (but not Class IIa) HDAC activities (assessed by Luminescent) with enhanced expressions of Class I (HDAC1, HDAC2, HDAC3, and HDAC8) but not Class IIb HDAC (HDAC6 and HDAC10) proteins in HL-1 cells. TNF-α induced mitochondrial dysfunction with impaired basal, ATP-linked, and maximal respiration, decreased cellular ATP synthesis, and increased mitochondrial superoxide production (measured by MitoSOX red fluorescence), which were rescued by inhibiting HDACs with MPT0E014 (1 μM, a Class I and IIb inhibitor), or MS-275 (1 μM, a Class I inhibitor). MPT0E014 reduced TNF-α-decreased complex I and II enzyme (but not III or IV) activities (by enzyme activity microplate assays). Our results suggest that Class I HDAC actions contribute to TNF-α-induced mitochondrial dysfunction in cardiomyocytes with altered complex I and II enzyme regulation. HDAC inhibition improves dysfunctional mitochondrial bioenergetics with attenuation of TNF-α-induced oxidative stress, suggesting the therapeutic potential of HDAC inhibition in cardiac dysfunction.

KEYWORDS:

• Mitochondria
• histone deacetylase inhibition
• bioenergetics

Acknowledgements

This work was supported by grants from the Ministry of Science and Technology (MOST105-2628-B-038-012-MY3, and MOST 105-2314-B-038-059-MY3), Taipei Medical University-Wan Fang Hospital (104swf02, 104-wf-eva-01, 105-wf-eva-08 and 105-wf-eva-14).

Disclosure of interest

The authors report no conflict of interest.

Additional information

Funding

Taipei Medical University-Wan Fang Hospital Ministry of Science and Technology, Taiwan This work was supported by the Ministry of Science and Technology, Taiwan [grant number MOST 105-2314-B-038-059-MY3], [grant number MOST105-2628-B-038-012-MY3]; Taipei Medical University-Wan Fang Hospital [grant number 105-wf-eva-14].