Abstract Lack of the adiponectin target receptor adiponectin receptor 1 (AdipoR1) impairs gene expression of mitochondrial OXPHOS proteins due to impaired AMPK-SIRT1-PGC-1α signaling. Since decreased adiponectin serum levels in diabetes mellitus should thus compromise AdipoR1 signaling, we hypothesized that impaired AdipoR1 signaling may causally contribute to typically observed mitochondrial defects in diabetes complications. Thus, we performed comparative proteomics in cardiac, renal and hepatic tissue of AdipoR1−/− mice using LC-MS/MS. Using principal component analysis, heatmapping and hierarchical clustering, a significant separation of genotypes was observed across tissues. Enrichment analysis of differentially expressed proteins revealed disproportionate representation of proteins involved in oxidative phosphorylation, TCA cycle and fatty acid oxidation in all tissues. While 121 or 98 or 78 proteins were differentially regulated in cardiac or renal or hepatic tissue, respectively, only 15 proteins were regulated in the same direction across all tissues. Pathway analysis identified HNF4, NRF1, LONP, RICTOR, SURF1, insulin receptor and PGC-1α as most likely upstream regulators. Importantly, we found a dramatic downregulation of AdipoR1 expression in heart (−70%), liver (−90%) and kidney (−80%; all p<0.05) of high fat-fed and prediabetic non-transgenic mice compared to low fat-fed mice. In addition and beyond diabetes, AdipoR1 expression was also decreased in endstage failing hearts of non-diabetic human subjects compared to non-failing donor hearts. Thus, we conclude that AdipoR1 signaling regulates mitochondrial protein composition across all tissues in a functionally conserved, yet molecularly distinct, manner. Impaired AdipoR1 signaling may causally contribute to mitochondrial defects in diabetic complications and even human heart failure.