Investigating the molecular basis for the impaired mitochondrial dynamics in Barth syndrome 

Halil Aydin, DVM, PhD, University of Colorado, Boulder 

Idea Award, $40,000, over one year 

 Mitochondria are essential cellular compartments in all cells responsible for making cellular energy. In heart muscle cells, mitochondria produce significant amounts of energy in the form of ATP to sustain normal cardiac function. In addition to their role in energy production, mitochondria are involved in the processes driving production of amino acids, lipids, and nucleotides, the transport of metabolites and ions, regulated cell death, and cellular communication; this process is known as cellular metabolism. These processes are required for adapting to energy demands and preserving balance in cardiac cells. Barth syndrome is an important X-linked disease characterized by cardiomyopathy and perturbations in an important mitochondrial fat/lipid called cardiolipin (CL). Loss of mature CL or accumulation of an immature CL called monolyso-cardiolipin (MLCL) results in defects in cardiac muscle cells, which are very energy-dependent and particularly vulnerable to mitochondrial dysfunction. CL molecules interact with several key proteins in mitochondria and play a central role in a plethora of metabolic and regulatory processes that determine cell function and fate. Optic atrophy 1 (OPA1) is a mitochondrial mechano-chemical enzyme, which targets the mitochondrial membranes in a CL-dependent manner to regulate mitochondrial structure and dynamics. Moreover, OPA1 influences many biological processes, including cellular differentiation and survival, energy production, and regulated cell death. Molecular abnormalities in OPA1’s function result in aberrant mitochondrial structure, impaired energy production, and the development of a growing list of cardiovascular disorders. Yet, the mechanisms connecting MLCL accumulation and regulation of mitochondrial form and function remain poorly understood. In this grant, we will investigate the mechanisms governing mitochondrial function by characterizing how CL and OPA1 interact and provide a critical molecular understanding how MLCL accumulation results in mitochondrial dysfunction in Barth Syndrome. Together, our findings will provide a biochemical framework for understanding the role of mitochondrial dynamics in Barth syndrome and highlight an important step toward exploring the pathophysiology of Barth syndrome and related clinical therapeutics.