Interplay of packing and flip-flop in local bilayer deformation. How phosphatidylglycerol could rescue mitochondrial function in a cardiolipin-deficient yeast mutant

TL;DR

This study investigates how phosphatidylglycerol can compensate for cardiolipin deficiency in mitochondria by affecting membrane deformation, revealing lipid-specific roles in mitochondrial function through experimental and simulation approaches.

Contribution

It demonstrates that phosphatidylglycerol promotes membrane tubulation via flip-flop mechanisms, explaining its ability to rescue mitochondrial activity in cardiolipin-deficient yeast mutants.

Findings

Phosphatidylglycerol induces longer, pearled tubules with extended lifetimes.

Inward PG flip-flop is promoted by local pH gradients, affecting membrane morphology.

Yeast mutants with phosphatidylglycerol accumulation maintain mitochondrial activity despite cardiolipin deficiency.

Abstract

In a previous work, we have shown that a spatially localized transmembrane pH gradient, produced by acid micro-injection near the external side of cardiolipin-containing giant unilamellar vesicles, leads to the formation of tubules that retract after the dissipation of this gradient. These tubules have morphologies similar to mitochondrial cristae. The tubulation effect is due to direct phospholipid packing modification in the outer leaflet that is promoted by protonation of cardiolipin headgroups. Here we compare the case of cardiolipin-containing giant unilamellar vesicles with that of phosphatidylglycerol-containing giant unilamellar vesicles. Local acidification also promotes formation of tubules in the latter. However, compared to cardiolipin-containing giant unilamellar vesicles the tubules are longer, exhibit a visible pearling and have a much longer lifetime after acid micro-injection is stopped. We attribute these differences to an additional mechanism that increases monolayer surface imbalance, namely inward PG flip-flop promoted by the local transmembrane pH-gradient. Simulations using a fully non-linear membrane model as well as geometrical calculations are in agreement with this hypothesis. Interestingly, among yeast mutants deficient in cardiolipin biosynthesis, only the crd1-null mutant, which accumulates phosphatidylglycerol, displays significant mitochondrial activity. Our work provides a possible explanation of such a property and further emphasizes the salient role of specific lipids in mitochondrial function.