Hepatic mitochondria organization and functions

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Mitochondrial functions extend beyond energy production. They are involved in vital cellular processes including differentiation, calcium homeostasis, bioenergetics, apoptosis, and autophagy. Additionally, mitochondria can adjust their metabolic output in response to environmental factors, allowing cells to adapt and restore homeostasis. However, chronic exposure to the unfavorable conditions caused by nutrient excess gives rise to mitochondrial dysfunction as observed in Non-Alcoholic Fatty Liver Disease (NAFLD). Yet, whether this dysfunction is primary or secondary to NAFLD is still unclear. A major obstacle in addressing this question is the difficulty of evaluating mitochondrial functions in vivo and the inability to recapitulate the tissue environment using in vitro models. Moreover, several studies uncovered in recent years a remarkable heterogeneity in mitochondrial form and function in vivo revealing our limited understanding of organization and activities in the three-dimensional setting of tissues. Our goal is to understand hepatic mitochondria organization and functions in physiology and diet-induced metabolic stress. To this aim, we study mitochondria in the intact liver with respect to liver anatomy (Cunningham and Porat-Shliom 2021). Specifically, hepatocytes are organized in a hexagonal unit called the hepatic lobule. In each lobule, blood enters at the corners (periportal regions; PP) and flows directionally towards the central vein (pericentral regions; PC). As a result, hepatocytes along the PP-PC axis are exposed to a different environment depending on their location with respect to the portal vessels, a phenomenon known as liver zonation. This differential environment drives the spatial compartmentalization of metabolism, however, the functional consequences of liver zonation and how it impacts mitochondrial function were never examined. We use a combination of microscopy, mouse genetics, and spatially resolved biochemistry to decipher mechanisms of hepatic mitochondrial functions and dysfunctions in vivo. Our studies provide tissue scale insights into mitochondrial spatial diversification and their remodeling in response to changes in nutrient supply. Our work begins to capture the complexity of mitochondria heterogeneity and plasticity in intact tissue and during physiological metabolic transitioning.