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

• Published in: Nature communications 2024-02, Vol.15 (1), p.1799-1799, Article 1799
• Main Authors: Kang, Sun Woo Sophie, Cunningham, Rory P., Miller, Colin B., Brown, Lauryn A., Cultraro, Constance M., Harned, Adam, Narayan, Kedar, Hernandez, Jonathan, Jenkins, Lisa M., Lobanov, Alexei, Cam, Maggie, Porat-Shliom, Natalie
• Format: Article
• Language: English
• Subjects: 14; 14/19; 14/28; 631/443/319; 631/80/642/333; 631/80/86/2369; 82/58; Heterogeneity; Homeostasis; Humanities and Social Sciences; Lipids; Liver; Liver - metabolism; Liver diseases; Mitochondria; Mitochondria - metabolism; multidisciplinary; Nutrient availability; Nutrient concentrations; Nutrients; Oxidation; Oxidation-Reduction; Pharmaceuticals; Phenotypes; Phosphorylation; Protein structure; Proteomics; Science; Science (multidisciplinary); Structure-function relationships; TOR protein; Zonation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45751-9

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. Kang et al. reveal structural and functional differences in mitochondria across the hepatic lobule. Mitochondrial distinct phosphoproteome influences their functions highlighting how nutrient availability helps to shape mitochondria zonation.