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

作者：Sun Woo Sophie Kang, Rory P. Cunningham, Colin B. Miller, Lauryn A. Brown, Constance M. Cultraro, Adam Harned, Kedar Narayan, Jonathan M. Hernandez, Lisa M. Jenkins, Alexei Lobanov, Maggie Cam, Natalie Porat‐Shliom · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2023 · DOI：10.1101/2023.04.13.536717 · 被引用次数：8 · 研究领域：Mitochondrial Function and Pathology、Diet and metabolism studies、Adipose Tissue and Metabolism

In the liver, mitochondria are exposed to different concentrations of nutrients due to their spatial positioning across the periportal (PP) and pericentral (PC) axis. How these mitochondria sense and integrate these signals to respond and maintain homeostasis is not known. Here, we combined intravital microscopy, spatial proteomics, and functional assessment to investigate mitochondrial heterogeneity in the context of liver zonation. We found that PP and PC mitochondria are morphologically and functionally distinct; beta-oxidation was elevated in PP regions, while lipid synthesis was predominant in the PC mitochondria. In addition, comparative phosphoproteomics revealed spatially distinct patterns of mitochondrial composition and potential regulation via phosphorylation. Acute pharmacological modulation of nutrient sensing through AMPK and mTOR shifted mitochondrial phenotypes in the PP and PC 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.