Research

Acylations: a novel pathway in the response to mitochondrial energy dysfunction.

Primary mitochondrial disorders arising from primary defects in the mitochondrial energy production machinery are the most common form of inborn errors of metabolism and often impact high-energy tissues like the heart. Approximately one-third of mitochondrial disease patients present with cardiac diseases such as hypertrophic cardiomyopathies. To date, there is no cure for mitochondrial disorders and no therapies designed specifically to address associated cardiomyopathy. Identifying molecular pathways activated in response to mitochondria energy defects may hold the key to the development of therapies for these incurable disorders.

This project leverages a mouse model with cardiomyocyte-specific and inducible deletion of the mitochondrial phosphate carrier (SLC25A3) as a novel approach to study the molecular consequences of mitochondrial energy dysfunction in the heart. Cardiac-specific SLC25A3-deleted mice have impaired ATP synthesis and develop severe hypertrophic cardiomyopathy similar to that in human patients with mitochondrial phosphate carrier deficiency (MPCD) caused by SLC25A3 mutations.

We discovered that SLC25A3 deletion-induced mitochondrial energy dysfunction results in a striking and distinct signature of acylome remodeling, with a progressive accumulation of post-translational acetylation and malonylation on mitochondrial proteins. Ongoing work in the lab is aimed at delineating the mechanisms underlying SLC25A3 deletion/mitochondrial energy dysfunction-induced mitochondrial acetylome and malonylome remodeling and the consequences of these modifications on cardiac function and disease.