Mithocondrial Regulation of Cell Death

In the last years, our group has focused on the role of structural lipids in cell signaling and human disease. Our work has added a new dimension to the classic view of lipids as mere structural components of bilayers by describing the critical roles that cholesterol and sphingolipids (SL) play in the regulation of cell death by targeting mitochondrial membranes, leading to the progression of prevalent human diseases, including fatty liver disease (FLD) and its progression to liver cancer as well as in major neurodegenerative diseases, predominantly Alzheimer´s disease (AD) and lysosomal storage disorders, like Niemann-Pick type A and C.

We have unraveled the role of mitochondrial cholesterol trafficking in the above-mentioned diseases and discovered the upregulation of STARD1, a mitochondrial cholesterol transporter responsible for the trafficking of cholesterol to the mitochondrial inner membrane (MIM). STARD1 levels are rather low in the liver but they remarkably increase in pathological states, including steatohepatitis, an advanced stage of FLD, which encompasses both alcoholic (ASH) and non-alcoholic steatohepatitis (NASH) characterized by inflammation, fibrosis and hepatocellular demise, that can progress to hepatocellular carcinoma (HCC). As a proof of concept for the role of STARD1 in liver disease, we have generated STARD1 floxed mice to develop different mouse lines with deletion of STARD1 in hepatocytes and nonparenchymal cells (hepatic stellate cells and Kupffer cells). Its induction has been also identified as a critical player in drug-induced liver injury and has emerged as a novel therapeutic target to protect against acetaminophen hepatotoxicity. Similar to the liver diseases, we have described recently the induction of STARD1 in patients with AD and Down Syndrome—a genetically determined form of AD- while mice with genetic deletion of STARD1 in neurons are resistant to diet-induced AD-like symptoms. We have also investigated the role of SL in liver diseases and have identified acid sphingomyelinase as a mechanism for the rapid generation of ceramide in specific acidic compartments in both ASH and NASH, and have identified the acetylation status of GD3 as a determinant factor for liver fibrosis. Finally, our recent observations described a central role for the multiprotein complex NLRP3 inflammasome activated by mitochondrial cholesterol in NASH progression.

Currently, our research is organized into 3 main interdisciplinary lines to better understand the molecular mechanisms and the biology of these conditions, to design new drugs or to reuse existing ones for treatment. Our research groups are:

1. Lipid cell biology and impact in metabolic disorder (IP: Carmen Garcia-Ruiz)
2. Mitochondria as central hub of liver disease and neurodegeneration (IP: JC Fernandez-Checa)
3. Inflammasome activation and mitochondrial stress in NASH (IP: Sandra Torres)

The group is funded by national and international public and private agencies (ISCIII, MINECO, NIAAA, NIC, NIH, H2020, CIBEREHD, Marató TV3, BBVA, Mutua madrileña; AGAUR, AEEH, European Action COST, CSIC Cancer hub network, CSIC RER Biomed network, USA Strong together NPC Foundation)

Selected current funding:

NIC-NIH grant (2024-2029)

PID2023-148803OB-I00 (2024-2027)

H2020_HaltRONIN (2023-2027)

PID2022-145926OB-I00 (2023-2026)

PID2022-140169OB-C22 (2023-2026)

SGR00491 (2022-2026)

Selected active collaborations:

Ana Cenarro, University of Zaragoza

Cecilia Rodrigues, University of Lisbon

Francisco Javier Cubero, University Complutense of Madrid

Hidekazu Tsukamoto, University of Southern California

Ian Holt, University Collegue London

Isabel Lucena, University of Malaga

José Juan García Marín, University of Salamanca

Matías Avila, University of Navarra

Michael Karin, University of San Diego

Neil Kaplowitz, University of Southern California

Randal Kaufman, Neuroscience Center at Sanford Burnham Medical Institute

Sanda Win, Keck School of Medicine (USC)

Silvana Zanlungo, University Catholic of Chile

Linkedin:
https://www.linkedin.com/company/mithocondrial-regulation-of-cell-death-group-iibb-csic/

Past lab members:​