Abstract
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 meta-analysis 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 genome-wide 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.
Highlights
Mitochondria are highly abundant organelles, found in almost every eukaryotic cell, and are best known for production of adenosine triphosphate via oxidative phosphorylation
A mitochondrion-centric co-expression network was generated by searching the CO-Regulation Database (CORD) [29] for transcripts with expression signatures similar to those of bona fide mitochondrial protein-encoding transcripts (MPETs) (Fig 1A)
We used a predictive methodology based on gene co-expression to nominate proteins relevant to mitochondrial function in the context of the metabolic and signaling derangement associated with pathological cardiac hypertrophy
Summary
Mitochondria are highly abundant organelles, found in almost every eukaryotic cell, and are best known for production of adenosine triphosphate via oxidative phosphorylation. Mitochondrial diseases (MD) aggregately represent the most prevalent cause of inborn errors of metabolism and encompass a clinically heterogenous group of multisystemic disorders—with symptoms including myopathy, encephalopathy, lactic acidosis, neuropathy, liver failure, ataxia, deafness and optic atrophy—that result from defective mitochondrial function [3]. As well as highlighting the functional heterogeneity of the organelle, MitoCarta has enabled the identification of multiple disease-causing genes [12,13,14,15,16]. In addition to the proteins reported in the MitoCarta database and companion studies [17, 18], it is estimated that a substantial number, perhaps several hundred, remain unassigned and efforts to fill this gap continue
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
