Dysregulation of the Mitochondrial Proteome Occurs in Mice Lacking Adiponectin Receptor 1.

Mark E Pepin,Peter Stachon,Christoph Bode,Christoph Koentges,Michael M Hoffmann,Philipp Diehl,Katharina Pfeil,Johannes Gollmer,Katja E Odening,Sophia Kersting,Sebastian Wiese,Heiko Bugger,Adam R Wende,Dennis Wolf,Andreas Zirlik,Constantin Von Zur Mühlen

doi:10.3389/fendo.2019.00872

Abstract

Decreased serum adiponectin levels in type 2 diabetes has been linked to the onset of mitochondrial dysfunction in diabetic complications by impairing AMPK-SIRT1-PGC-1α signaling via impaired adiponectin receptor 1 (AdipoR1) signaling. Here, we aimed to characterize the previously undefined role of disrupted AdipoR1 signaling on the mitochondrial protein composition of cardiac, renal, and hepatic tissues as three organs principally associated with diabetic complications. Comparative proteomics were performed in mitochondria isolated from the heart, kidneys and liver of Adipor1−/− mice. A total of 790, 1,573, and 1,833 proteins were identified in cardiac, renal and hepatic mitochondria, respectively. While 121, 98, and 78 proteins were differentially regulated in cardiac, renal, and hepatic tissue of Adipor1−/− mice, respectively; only 15 proteins were regulated in the same direction across all investigated tissues. Enrichment analysis of differentially expressed proteins revealed disproportionate representation of proteins involved in oxidative phosphorylation conserved across tissue types. Curated pathway analysis identified HNF4, NRF1, LONP, RICTOR, SURF1, insulin receptor, and PGC-1α as candidate upstream regulators. In high fat-fed non-transgenic mice with obesity and insulin resistance, AdipoR1 gene expression was markedly reduced in heart (−70%), kidney (−80%), and liver (−90%) (all P < 0.05) as compared to low fat-fed mice. NRF1 was the only upstream regulator downregulated both in Adipor1−/− mice and in high fat-fed mice, suggesting common mechanisms of regulation. Thus, AdipoR1 signaling regulates mitochondrial protein composition across all investigated tissues in a functionally conserved, yet molecularly distinct, manner. The biological significance and potential implications of impaired AdipoR1 signaling are discussed.

Highlights

Adiponectin is an adipose-derived hormone which comprises 0.01% of all plasma proteins
To determine the impact of disrupted adiponectin receptor signaling on mitochondrial protein composition, a proteomicsbased analysis was performed using mitochondria-enriched protein lysate in Adipor1−/− relative to age-matched littermate controls
We identified a robust signature of proteins within cardiac [790], renal [1,573], and hepatic [1,833] tissues isolated from both Adipor1−/− and littermate controls (Table S3)

Summary

Introduction

Adiponectin is an adipose-derived hormone which comprises 0.01% of all plasma proteins. A common physiological intersection among these cascades is the regulation of mitochondrial function either by directly regulating substrate oxidation through modulation of enzymatic activity, or by controlling the gene expression of mitochondrial proteins via recruitment of PPARγ coactivator-1α (PGC-1α) [9, 11, 12]. Both in skeletal and cardiac muscles, deletion of AdipoR1 in mice impairs mitochondrial function, decreases gene expression of oxidative phosphorylation (OXPHOS) subunits, induces mitochondrial oxidative stress and decreases mitochondrial content, again mediated by disruptions in AMPK/SIRT1/PGC-1α signaling [6, 9]

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