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Biological/Clinical Application 4

PI:  Brian O'Rourke             Collaborator:  Robert Cotter

Mitochondrial acetylation in HF

Histone acetylation by histone acetyltransferase (HAT) and deacetylation by histone deacetylases (HDACs) is a central regulatory paradigm in the heart  in response to acute or chronic stress and is responsible for the re-expression of the fetal gene program and hypertrophic cardiac growth. Only recently has acetylation and deacetylation of non-nuclear, histone-independent targets emerged as a regulatory modality for mitochondrial proteins.

Overall Research Goal: We will define the role of acetylation in the mitochondria and the influence of HF.

Goal 1: Characterize the acetylases and deacetylases of cardiac mitochondria.

Rationale: Carry out an unrestricted screen of cellular acetyllysines revealed that a significant fraction of mitochondrial proteins are acetylated, yet only a few have been tied to a specific acetyltransferase.

Goal 2: Characterize the mitochondrial protein targets of acetylation with HF.

Rationale: It is presently unknown whether mitochondrial acetylation/deacetylation is altered by chronic metabolic stress.

Goal 3: Characterize the acute functional effects of selective activators and inhibitors of deacetylases and acetylases on the acetylproteome of isolated mitochondria from control and HF hearts.

Rationale: If sirtuins/HDACs or HATs mediate acute regulatory signaling by acetyllysine modification, then selective inhibition or activation of the enzymes should alter the acetylproteome.