Abstract
The mitochondria-associated membrane (MAM) is a specialized subdomain of the endoplasmic reticulum (ER) which acts as an intracellular signaling hub. MAM dysfunction has been related to liver disease. We report a high-throughput mass spectrometry-based proteomics characterization of MAMs from mouse liver, which portrays them as an extremely complex compartment involved in different metabolic processes, including steroid metabolism. Interestingly, we identified caveolin-1 (CAV1) as an integral component of hepatic MAMs, which determine the relative cholesterol content of these ER subdomains. Finally, a detailed comparative proteomics analysis between MAMs from wild type and CAV1-deficient mice suggests that functional CAV1 contributes to the recruitment and regulation of intracellular steroid and lipoprotein metabolism-related processes accrued at MAMs. The potential impact of these novel aspects of CAV1 biology on global cell homeostasis and disease is discussed.
Highlights
endoplasmic reticulum (ER)-resident proteins were differentially distributed: calreticulin and associated with lipid droplet protein 1 (ALDI) were partitioned between ER and Mitochondria-associated membranes (MAMs) fraction, but the acyl-CoA synthases ACSL1 and ACSL3 were highly reduced in MAMs compared to the bulk of the ER
In this work we describe for the first time the protein composition of highly purified hepatic MAM fractions and demonstrate that CAV1 is a MAM-resident protein
Our unprecedented profiling of hepatic MAMs confirms that several enzymes involved in lipid metabolism (in particular conversion of (S)-squalene,2-3-epoxyde to cholesterol, and biosynthesis of steroid derivatives) accrue at hepatocyte MAMs
Summary
MAMs may contribute to other major health threats such as hepatitis C infection and hepatocarcinoma, because of the pivotal relevance of aberrant inflammation and proteostasis signaling in these pathologies[3]. Fatty acid catabolism and steroid metabolism appear among the most enriched functional classes annotated for liver MAM components, and we were able to map most key components of the cholesterol/steroid biosynthesis and transport pathways. We found caveolin-1 (CAV1), a pivotal regulator of cholesterol intracellular transport and membrane organization, as an specific integral component of MAMs. Because of the relevance of CAV1 for mitochondrial functioning, lipidostasis and metabolic homeostasis[5,6], and for the control of numerous signaling pathways integrated at MAMs7, we performed a comparative structural and compositional study between wild type ( WT) and CAV1-deficient mice (CAV1KO). The potential relevance and future avenues of research suggested by the present framework are discussed
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