# Src-mediated PHB2 phosphorylation disrupts mitochondrial cristae through cardiolipin dissociation in hepatocellular carcinoma

## TL;DR

This study shows how Src kinase disrupts mitochondrial structure in liver cancer, leading to metabolic changes that fuel tumor growth.

## Contribution

The novel finding is that Src-mediated PHB2 phosphorylation disrupts mitochondrial cristae through cardiolipin dissociation in hepatocellular carcinoma.

## Key findings

- Src phosphorylates PHB2 at Y34 and Y77, causing PHB1/2 complex disassembly and OMA1 activation.
- PHB2 phosphorylation leads to OPA1 cleavage, cristae remodeling, and impaired electron transport chain function.
- Phosphomimetic PHB2 mutants worsen tumor growth, while phosphorylation-resistant mutants suppress it.

## Abstract

Hepatocellular carcinoma (HCC) displays mitochondrial dysfunction characterized by disrupted redox homeostasis and cristae disorganization, yet the underlying molecular mechanisms are unclear. We reveal that Src kinase phosphorylates prohibitin 2 (PHB2) at tyrosines Y34 and Y77 under oxidative stress, disrupting its interaction with cardiolipin and triggering PHB1/2 complex disassembly. This event activates the mitochondrial protease OMA1, promoting excessive cleavage of the cristae-shaping protein OPA1, leading to severe cristae remodeling. Consequent impairment of electron transport chain supercomplexes decreases NAD+/NADH ratio and complex I/II activities, creating conditions that promote enhanced electron leakage and oxidative stress. This mitochondrial dysfunction drives a metabolic shift from oxidative phosphorylation toward glycolysis, promoting tumor growth in xenograft models. Phosphomimetic PHB2 mutants (Y34E/Y77E) exacerbate these effects, whereas phosphorylation-resistant mutants (Y34F/Y77F) restore cristae integrity, normalize redox balance, and suppress tumor progression. Our findings establish Src-mediated PHB2 phosphorylation as a redox-sensitive molecular switch that drives HCC metabolic reprogramming by disrupting the PHB2-cardiolipin cristae axis. This phosphorylation event represents a targetable vulnerability for this malignancy with limited treatment options.

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