Biology subjects

Cunningham, R. P.

Publications and source records attributed to Cunningham, R. P..

2 recordsLinked to original sources

bioRxiv2023

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

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.

cell biology↗

bioRxiv2022

LKB1 acts as a critical brake for the glucagon-mediated fasting response

As important as the fasting response is for survival, an inability to shut it down once nutrients become available can lead to exacerbated disease and severe wasting. The liver is central to transitions between feeding and fasting states, with glucagon being a key initiator of the hepatic fasting response. However, the precise mechanisms controlling fasting are not well defined. One potential mediator of these transitions is Liver Kinase B1 (LKB1) given its role in nutrient sensing. Here, we show LKB1 knockout mice have a severe wasting and prolonged fasting phenotype despite increased food intake. By applying RNA sequencing and intravital microscopy we show that loss of LKB1 leads to a dramatic reprogramming of the hepatic lobule through robust upregulation of periportal genes and functions. This is likely mediated through the opposing effect LKB1 has on glucagon pathways and gene expression. Conclusion: our findings show that LKB1 acts as a brake to the glucagon-mediated fasting response resulting in "periportalization" of the hepatic lobule and whole-body metabolic inefficiency. These findings reveal a new mechanism by which hepatic metabolic compartmentalization is regulated by nutrient-sensing.

physiology↗