Targeting mitochondrial phosphatidylethanolamine alters mitochondrial metabolism and proliferation in hepatocellular carcinoma

TL;DR

This study shows that altering mitochondrial phosphatidylethanolamine disrupts metabolism and cell growth in liver cancer.

Contribution

The study reveals a novel role of mitochondrial phosphatidylethanolamine in hepatocellular carcinoma metabolism and proliferation.

Findings

Silencing PISD impairs mitochondrial metabolism and reduces electron transport chain abundance in HCC cells.

PISD deficiency increases mitochondrial superoxide and alters mitochondrial dynamics through fission and mitophagy.

Reduced mitochondrial PE decreases DNA synthesis and cell proliferation via mTOR signaling suppression.

Abstract

Mitochondrial metabolism is crucial for hepatocellular carcinoma (HCC) to thrive. Although phospholipids modulate mitochondrial metabolism, their impact on metabolism in HCC remains unknown. Here we report that the mitochondrial phospholipidome is unaltered in HCC mitochondria, suggesting HCC maintain their mitochondrial phospholipidome to enable efficient metabolism and promote thriftiness. Consistent with this, silencing phosphatidylserine decarboxylase (PISD), the inner mitochondrial membrane protein that generates mitochondrial phosphatidylethanolamine (PE), in HEPA1-6 cells impairs mitochondrial metabolism of fatty acid and glucose-derived substrates and reduces electron transport chain I and IV abundance. Moreover, PISD deficiency increased mitochondrial superoxide generation and altered mitochondria dynamics by augmenting mitochondrial fission, mitophagy, and mitochondrial extracellular efflux. Despite compensatory increases in anaerobic glycolysis and peroxisome fat oxidation, mitochondrial PE deficiency reduced DNA synthesis and cell proliferation, effects associated with reduced mTOR signaling and peptide levels. We conclude that targeting mitochondrial PE synthesis may be a viable therapy to slow HCC progression.

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