The hepatic mitochondrial landscape

Abstract

Mammalian energy homeostasis depends on coordinated metabolism across tissues, with the liver acting as a central hub for systemic energy balance and biosynthetic precursor supply. Although hepatic mitochondrial dysfunction is implicated in diverse pathologies, mitochondrial regulation across liver microanatomical space and time remains incompletely defined. Here, we mapped how mitochondrial- and nuclear-encoded genes supporting mitochondrial function vary along spatial gradients within the lobule and across the feeding-fasting cycle in mice. Integrating these transcriptomic features with quantitative measurements of mitochondrial morphology in periportal and pericentral hepatocytes, we showed that functional hepatocyte subtypes are distinguished by pronounced mitochondrial divergence, including cells with exceptionally low mitochondrial gene expression and reduced secretory protein production. We described that higher periportal oxidative phosphorylation relies on an exceptionally high periportal mitochondrial transcript fraction, while nuclear mitochondrial-function genes do not follow this pattern. The increased periportal mitochondrial transcript abundance coincided with substantially increased periportal cytoplasmic mitochondrial density. In humans, we recapitulated the higher periportal mitochondrial transcript abundance and showed that mitochondrial-function genes exhibited rhythmic expression patterns, more so in women. Together, these data establish a spatially and temporally resolved reference dataset of hepatic mitochondrial regulation that provides a reference for interpreting liver single-cell datasets and mechanistic pathophysiological studies.