A spatial map of hepatic mitochondria uncovers functional heterogeneity shaped by nutrient-sensing signaling

Abstract

In the liver, mitochondria are exposed to different concentrations of nutrients due to their spatial positioning across the periportal and pericentral axis. How the mitochondria sense and integrate these signals to respond and maintain homeostasis is not known. Here, we combine intravital microscopy, spatial proteomics, and functional assessment to investigate mitochondrial heterogeneity in the context of liver zonation. We find that periportal and pericentral mitochondria are morphologically and functionally distinct; beta-oxidation is elevated in periportal regions, while lipid synthesis is predominant in the pericentral mitochondria. In addition, comparative phosphoproteomics reveals spatially distinct patterns of mitochondrial composition and potential regulation via phosphorylation. Acute pharmacological modulation of nutrient sensing through AMPK and mTOR shifts mitochondrial phenotypes in the periportal and pericentral regions, linking nutrient gradients across the lobule and mitochondrial heterogeneity. This study highlights the role of protein phosphorylation in mitochondrial structure, function, and overall homeostasis in hepatic metabolic zonation. These findings have important implications for liver physiology and disease.

Tissue‐specific differences in Ca2+ sensitivity of the mitochondrial permeability transition pore (PTP). Experiments in male rat liver and heart

“…Brain mitochondria contain fewer and smaller mitochondria that kidney or liver, while the heart has the largest and most abundant mitochondria (Veltri et al., 1990 ). In heart and liver the mitochondrial reticulum organization is different (Aon et al., 2006 ; Kang et al., 2024 ). Even at the level of individual enzymes, the tissue‐specific expression of subunit in Cytochrome c oxidase reflects different basal energy requirement in each organ (Vogt et al., 2021 ), and the Ca 2+ efflux (Serna et al., 2022 ).…”

Guidelines for mitochondrial RNA analysis

“…Mature cells such as high-energy-demanding cardiomyocytes, neurons, and hepatocytes display spatially distinct mitochondrial subpopulations. 182 , 183 , 184 In cardiac cells, mitochondria are classified as subsarcolemmal, nuclear, and/or interfibrillar. Subsarcolemmal and nuclear mitochondria lack specific organization.…”