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

Sun Woo Sophie Kang, Rory P. Cunningham, Colin B. Miller, Lauryn A. Brown, Constance M. Cultraro, Adam Harned, Kedar Narayan, Jonathan Hernandez, Lisa M. Jenkins, Alexei Lobanov, Maggie Cam and Natalie Porat-Shliom ()
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Sun Woo Sophie Kang: National Institutes of Health (NIH)
Rory P. Cunningham: National Institutes of Health (NIH)
Colin B. Miller: National Institutes of Health (NIH)
Lauryn A. Brown: National Institutes of Health (NIH)
Constance M. Cultraro: National Institutes of Health (NIH)
Adam Harned: National Institutes of Health
Kedar Narayan: National Institutes of Health
Jonathan Hernandez: National Institutes of Health (NIH)
Lisa M. Jenkins: National Institutes of Health (NIH)
Alexei Lobanov: National Institutes of Health (NIH)
Maggie Cam: National Institutes of Health (NIH)
Natalie Porat-Shliom: National Institutes of Health (NIH)

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45751-9

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