Role of cardiolipin in cardiac ADP/ATP translocator activity

Nanami Senoo, PhD, Postdoctoral Fellow, Department of Physiology, Claypool Lab, Johns Hopkins University School of Medicine

Cardiolipin, a mitochondrial-specific phospholipid, is necessary for proper mitochondrial energy production. CL contains two headgroups and four fatty acyl-chains. Mutations in the TAZ gene, encoding an enzyme that remodels CL fatty acyl-chains, cause Barth syndrome (BTHS). BTHS patients present cardiac dysfunctions likely due to mitochondrial defects. The lack of TAZ-mediated remodeling activity in BTHS leads to complex CL abnormalities. However, the molecular details of how the CL abnormalities drive mitochondrial dysfunction and BTHS pathogenesis are unresolved. Adenine nucleotide translocator (ANT in mammals, AAC in yeast) transports ADP and ATP across the mitochondrial inner membrane; this is required for oxidative phosphorylation and ATP production. Of four isoforms of human ANT, ANT1 is dominantly expressed in the heart; however, it is undetermined if CL supports ANT1 activity. We recently demonstrated that CL supports multiple structural properties of Aac2, the major yeast isoform and the closest ortholog to ANT1. This proposed study will reveal structural and functional relationships between CL and ANT1 and understand their contributions to cardiac OXPHOS in BTHS. I will interrogate how CL molecules bound at three conserved ANT1 motifs and how cardiac-specific CL abnormalities in BTHS patients impact ANT1 structure and activity. Results generated may provide insight into tissue specificity of BTHS and determine the role of ANT1 in BTHS pathogenesis.

This fellowship was made possible by the AHA/BSF Research Partnership, and is a funding program for investigator-initiated career development and knowledge discovery projects that directly involve Barth syndrome or cardiolipin research. Administered and peer-reviewed by AHA's pre-doctoral and post-doctoral fellowship program, 2021 applications are due September 14th and 15th, respectively.