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Abstract 434: Cardiomyopathy-associated Point Mutation in the ADP-ATP Carrier Reveals Translation-dependent Regulation of Cytochrome
 c o
 xidase Activity in Yeast


 The interaction between the ADP/ATP carrier and the respiratory supercomplexes is evolutionarily-conserved, is dependent on cardiolipin, and is functionally significant as yeast lacking Aac2p have reduced activity of respiratory complex IV (
 cytochrome c oxidase
 or COX). We have leveraged a transport-dead pathogenic
 AAC2
 point mutant discovered in a patient with hypertrophic cardiomyopathy and mild myopathy to determine whether the reduction in complex IV activity in the absence of Aac2p reflects the absence of the interaction between Aac2p and components of the electron transport chain and/or the absence of nucleotide transport (i.e. Aac2p function). Importantly, the pathogenic A137D allele of
 AAC2
 is expressed normally and still interacts with components of the yeast respiratory supercomplex but is unable to support growth on respiratory media due to its inability to transport ADP/ATP. Amazingly, in the absence of Aac2p function, the expression levels of complex IV subunits that are encoded by the mitochondrial genome (and which form the catalytic core of the complex IV holoenzyme) are specifically reduced, even though assembly and interaction with the respiratory supercomplexes are preserved in the mutant Aac2p. This reduction in the levels of complex IV subunits is not caused by a reduction in either the mitochondrial genome copy number or the steady state level of mitochondrial DNA transcripts. Instead, there is a noticeable alteration in the pattern of the mitochondrial translation in the absence of Aac2p activity. Our results suggest that Aac2p function is important for normal translation of the mitochondrial encoded complex IV subunits and that Aac2p activity plays a significant role in regulating oxidative phosphorylation.
