Mitochondrial dysfunction contributes to myriad monogenic and complex pathologies. To
understand the underlying mechanisms, it is essential to define the full complement of proteins
that modulate mitochondrial function. To identify such proteins, we performed a metaanalysis
of publicly available gene expression data. Gene co-expression analysis of a large
and heterogeneous compendium of microarray data nominated a sub-population of transcripts
that whilst highly correlated with known mitochondrial protein-encoding transcripts
(MPETs), are not themselves recognized as generating proteins either localized to the mitochondrion
or pertinent to functions therein. To focus the analysis on a medically-important
condition with a strong yet incompletely understood mitochondrial component, candidates
were cross-referenced with an MPET-enriched module independently generated via genomewide
co-expression network analysis of a human heart failure gene expression dataset. The
strongest uncharacterized candidate in the analysis was Leucine Rich Repeat Containing 2
(LRRC2). LRRC2 was found to be localized to the mitochondria in human cells and transcriptionally-regulated
by the mitochondrial master regulator Pgc-1α. We report that Lrrc2 transcript
abundance correlates with that of β-MHC, a canonical marker of cardiac hypertrophy in
humans and experimentally demonstrated an elevation in Lrrc2 transcript in in vitro and in
vivo rodent models of cardiac hypertrophy as well as in patients with dilated cardiomyopathy.
RNAi-mediated Lrrc2 knockdown in a rat-derived cardiomyocyte cell line resulted in enhanced
expression of canonical hypertrophic biomarkers as well as increased mitochondrial mass in
the context of increased Pgc-1α expression. In conclusion, our meta-analysis represents a
simple yet powerful springboard for the nomination of putative mitochondrially-pertinent proteins relevant to cardiac function and enabled the identification of LRRC2 as a novel mitochondrially-relevant
protein and regulator of the hypertrophic response.