Interplay between hepatic mitochondria-associated membranes, lipid metabolism and caveolin-1 in mice

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.Grant support: M.A.d.P. was supported by grants SAF2011-25047, SAF2014-51876-R, and CSD2009-0016 from Spanish Ministry of Economy and Competitiveness (MINECO), 674/C/2013 from Fundacio La Marato de TV3, and AICR 15-0404 from the Worldwide Cancer Research Foundation. A.P. was supported by BFU2011-23745 and CSD2009-00016 from MINECO, and La Marato de TV3. A. S.-V., who is currently holding a Miguel Servet I contract (Instituto de Salud Carlos III, Spain), was a post-doctoral fellow at CNIC from Jan 2011 to Jan 2012 thanks to a Sara Borrell contract (Instituto de Salud Carlos III, Spain). I. N.-L. was supported by a postdoctoral fellowship from the Asociacion Espanola Contra el Cancer (AECC). The CNIC is supported by MINECO and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S