Cell-type-specific ER-Mitochondria contact sites in NAFLD Progression and Recovery

• Applicant: Professor Dr. Hans Zischka
• Subject Area: Anatomy and Physiology ; Biochemistry ; Gastroenterology ; Cell Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 530133784

CEMPR focuses on a highly relevant, but hardly investigated pathologic key mechanism in the increasingly occuring Non-alcoholic fatty liver disease (NAFLD). CEMPR will resolve whether mitochondria-associated membranes (MAM) play causal roles in dysfunction of the liver’s non-parenchymal cells (NPCs) and whether targeting MAMs can promote recovery from various stages of NAFLD. In three work packages (WP), we will investigate MAM dynamics and mitochondrial function in the liver’s NPCs in mouse models of NAFLD development and reversal. We will apply molecular spacer and linker strategies to regulate MAMs and mitochondrial function in different NPC lineages to evaluate functional specificity. Lastly, a clinical WP will be dedicated to 1) confirming mechanistic conservation; and 2) evaluation of MAM-related molecular signatures for future translatability. Based on our main hypothesis that a cell-type-specific disruption of mitochondria-endoplasmic reticulum contact sites induces NAFLD progression and influences the recovery process, we will answer the following three key hypotheses: 1. MAMs are regulated in NPCs and hepatocytes in the progression and reversal of NAFLD in vivo 2. Modulating MAMs in NPC lineages alters mitochondrial function and responses to stress in vitro 3. Mechanisms are conserved in humans and are represented by MAM-related molecular signatures.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partners: Dr. Fawaz Alzaid; Professorin Dr. Cyrielle Caussy, Ph.D.; Dr. Marie Lagouge, Ph.D.