How mitochondrial energy metabolism is controlled

More research on this protein’s role can also contribute to a better understanding of various diseases caused by mitochondrial dysfunction / publication in Molecular Cell.

A collaborative study (DOI:10.1016/j.molcel.2025.05.036) 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 (Faculty of Mathematics and Natural Sciences, University of Cologne) and Dr Simon Pöpsel at the Center for Molecular Medicine Cologne (CMMC), has been published in the journal Molecular Cell under the title “Interaction with AK2A links AIFM1 to cellular energy metabolism” (DOI). 

Combining cell biology, functional biochemistry and advanced structural biology, the study focusses on AIFM1, a protein critical for functioning of mitochondria – the cell’s energy-producing organelles. Mitochondria are often referred to as the ‘powerhouses’ of the cell, 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.

Defective 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 fulfils 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 Simon Pöpsel comments. 

“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 Jan Riemer adds. 

Find out more about Prof Dr Jan Riemer and Dr Simon Pöpsel by following this link
 

Original Publication
Robin Alexander Rothemann, Egor Pavlenko, Mrityunjoy Mondal, Sarah Gerlich, Pavel Grobushkin, Sebastian Mostert, Julia Racho, Konstantin Weiss, Dylan Stobbe, Katharina Stillger, Kim Lapacz, Silja Lucia Salscheider, Carmelina Petrungaro, Dan Ehninger, Thi Hoang Duong Nguyen, Jörn Dengjel, Ines Neundorf, Daniele Bano, Simon Poepsel, Jan Riemer, “Interaction with AK2A links AIFM1 to cellular energy metabolism”, Molecular Cell, 2025
DOI: 10.1016/j.molcel.2025.05.036

Scientific Contact

Dr Simon Pöpsel
s.poepsel[at]uni-koeln.de

Prof Dr Jan Riemer
jan.riemer[at]uni-koeln.de 

This message has been modified by the CMMC (K. Heber & D. Grosskopf-Kroiher) and is based on the text by the press and communications team of the University of Cologne (Anna Euteneuer, original version here).