HMN 2026: How Molecular machinery in cardiac mitochondria reacts to metabolic stress in unexpected way

In a recent study published in Nature Communications, researchers at Karolinska Institutet report that the molecular machinery responsible for cellular energy conversion is more interconnected than previously understood, shedding light on how mitochondria adapt under stress.

Mitochondria generate most of the cell’s energy by converting nutrients into ATP, the molecule that powers nearly all cellular processes. Although ATP synthase and metabolic pathways such as the tricarboxylic acid (TCA) cycle have long been known to work together, they have generally been viewed as separate systems.

Physical interactions revealed

In the new study, researchers at Karolinska Institutet, together with Professor Albert Heck’s group at Utrecht University, used advanced proteomics to map interactions in heart mitochondria. They found that ATP synthase physically associates with several enzymes of the TCA cycle.

“Using advanced proteomics approaches, we found that ATP synthase physically associates with several TCA cycle enzymes in heart mitochondria,” says Nils-Göran Larsson, professor in the Department of Medical Biochemistry and Biophysics at Karolinska Institutet and one of the corresponding authors. “This suggests that energy conversion and metabolism are more closely coordinated than previously thought.”

Changes during mitochondrial stress

The team also examined what happens when mitochondrial gene expression is impaired. In mouse models, this led to substantial remodeling of ATP synthase and stronger interactions with metabolic enzymes. At the same time, the inhibitory protein ATIF1 became more closely associated with ATP synthase, which may help cells conserve energy.

“We found that ATP synthase does not operate in isolation but adapts its interactions when mitochondrial function is impaired,” says Jelena Misic, postdoctoral researcher in the Department of Medical Biochemistry and Biophysics at Karolinska Institutet and one of the first authors of the study.

The findings provide new insight into how mitochondria reorganize their molecular machinery in response to bioenergetic stress. A better understanding of these adaptive changes may help researchers uncover the mechanisms underlying mitochondrial diseases.

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