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Protein AIFM1 emerges as a central coordinator of mitochondrial energy metabolism

A collaborative study from the University of Cologne has uncovered how a key mitochondrial protein, AIFM1 (Apoptosis-Inducing Factor Mitochondria-Associated 1), acts as a central hub in the regulation of cellular energy production.

The research, conducted by the teams of Professor Dr. Jan Riemer at the Institute of Biochemistry of the Faculty of Mathematics and Natural Sciences and Dr. Simon Pöpsel at the Center for Molecular Medicine Cologne (CMMC), has been in the journal Molecular Cell under the title "Interaction with AK2A links AIFM1 to cellular energy metabolism."

Combining cell biology, functional biochemistry and advanced structural biology, the study focuses on AIFM1, a protein critical for the functioning of mitochondria—the cell's energy-producing organelles. Mitochondria are responsible for producing adenosine triphosphate (ATP), the primary energy currency in biological systems. Proper mitochondrial function is essential for the health of energy-demanding tissues such as the brain, heart and muscles.

Defects in mitochondrial processes can lead to a range of disorders, collectively known as mitochondrial diseases, which may manifest as neurodegenerative conditions, muscular disorders or metabolic syndromes.

While AIFM1 was previously recognized for its roles in programmed cell death and respiratory chain assembly, this research expands that understanding by mapping its network of interaction partners. Most prominently, interaction with components of the MICOS complex and adenylate kinase 2 (AK2) links AIFM1 to the establishment of mitochondrial morphology and maintenance of energy homeostasis.

Using state-of-the-art cryo-electron microscopy (cryo-EM), the researchers visualized AIFM1 complexes in unprecedented detail. The resulting atomic models revealed how AIFM1 fulfills its roles as a central coordinator within the mitochondria. The researchers showed that AIFM1 stabilizes AK2A by binding to its C-terminal tail and that it positions AK2A close to ATP-transporting proteins and the ATP-generating ATP-synthase, thereby collectively contributing to increasing the efficiency of mitochondrial energy production.

"One of the study's key findings is the discovery of an interaction between AIFM1 and a variant of AK2A, an enzyme critical for maintaining the balance of adenine nucleotides such as ATP—the cell's main energy currency," Dr. Pöpsel states.

"We visualized these protein complexes at high resolution, enabling the construction of detailed atomic models. Our findings not only highlight AIFM1's role in supporting AK2A but also reveal its function as a central molecular hub, interacting with other key regulators of mitochondrial energy metabolism, including MIA40, the MICOS complex, ADP/ATP translocases, and ATP synthase," Professor Riemer adds.