Mitochondria self-regulate energy production via pH

Inside every cell, enzymes in the mitochondria cooperate to produce energy via the citric acid cycle (TCA cycle). Two of those enzymes are malate dehydrogenase (MDH1) and citrate synthase (CIT1). They can form a temporary complex, called a metabolon. In this complex, one enzyme passes its product directly to the next, making the cycle more efficient.

Complex forms and dissolves depending on activity

The researchers, working with yeast cells and publishing in eLife, showed that this MDH1-CIT1 complex is dynamic. When cells switch from aerobic respiration (oxygen use) to a less active state, the complex dissolves. When respiration is activated, it re-forms. Pharmacological inhibition of the TCA cycle broke the complex apart. Inhibiting the electron transport chain, the system that shuttles electrons to generate energy, strengthened the interaction instead.

What holds the complex together or drives it apart turns out to be connected to the acidity and oxidation state of the mitochondrial matrix, the interior of the mitochondrion. Even a small shift in pH, within the physiological range of 6.0 to 7.0, alters how strongly the two enzymes bind. The concentrations of intermediate metabolites such as malate, fumarate, and citrate also play a role.

Relevance for aging

Mitochondrial dysfunction is one of the most consistently described features of cellular aging. As cells age, the electron transport chain deteriorates and pH regulation in mitochondria changes. Whether the dynamics of the MDH1-CIT1 complex play a role in that process is not shown by this study. But the mechanism offers a new angle for understanding how mitochondria adapt their output to changing conditions, and what goes wrong during aging and disease.

This is basic research in yeast cells. Follow-up studies in human cells are needed to establish translatability.

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