1. Research Background

Metabolism is essential for cell survival, growth, and function, and is organized into complex networks of biochemical reactions involving metabolites and enzymes. Mitochondria lie at the center of metabolism, functioning far beyond ATP production. They coordinate and integrate different metabolic pathways, modulate cellular redox balance, and regulate levels of key metabolites that impact gene expression and cellular differentiation. As stress sensors and signaling stations, mitochondria adapt their composition and outputs to cellular changes in nutrients, oxygen, and organelle health, and signal to the nucleus and other organelles to orchestrate adaptive responses. Understanding mitochondrial control of cellular metabolism and redox homeostasis offers promising avenues for targeting disease-specific vulnerabilities and advancing regenerative medicine.

2. Research questions addressed by the group:

How do mitochondria signal their functional state to the remainder of the cell? How do mitochondria and cells cope with redox signals and redox stress? How do metabolites crosstalk with redox signals to regulate mitochondrial functions in particular mitochondrial protein import? These are some of the central research questions that currently drive research in our group. By tackling these questions, we have identified parameters controlling redox signaling within and from mitochondria, and have found key roles for proteins of the mitochondrial intermembrane space in controlling mitochondrial function, cellular metabolism, and mitochondrial protein import. Our discoveries revealed exciting novel regulatory principles that allow understanding mitochondrial functions during metabolic network state changes in healthy and perturbed conditions.

3. Possible project(s):

• Metabolic regulation of protein import into the mitochondrial intermembrane space. How does the cell’s metabolic state impact which proteins reach the mitochondrial intermembrane space?
• Redox regulation of the mitochondrial outer and inner membrane proteomes. What if the redox environment of intermembrane space and cytosol could fine-tune protein function and stability right at the mitochondrial surface or close to the respiratory chain?

4. Applied Methods and model organisms:

To address our research questions, we combine a diverse set of ´state-of-the-art` biochemical and cell biological methods in the lab. They include in vitro methods such as protein structure-function analyses with purified proteins and reconstitutions of novel enzymatic cascades. We also employ different cellular models to assess the dynamics of diverse metabolites and small redox molecules using genetically-encoded fluorescent sensors, to monitor the physiological consequences of redox regulation on cellular fitness and function, and to determine specific protein redox states often in combination with the genetic engineering of cells. Lastly, we utilize different high-throughput approaches including genetic screens, quantitative proteomics, targeted metabolomics, ribo-seq and transcriptomics.

5. Desirable skills and qualifications:

We are looking for a motivated, curious, and enthusiastic person with excellent basic knowledge in biochemistry, molecular and cell biology to join our collaborative group. Candidates should have demonstrated outstanding performance through their undergraduate studies and have a strong ability for problem solving through analytical thinking.

6. References and key publications:

1. Rothemann RA, Pavlenko E, Mondal M, Gerlich S, Grobushkin P, Mostert S, Racho J, Weiss K, Stobbe D, Stillger K, Lapacz K, Salscheider SL, Petrungaro C, Ehninger D, Nguyen THD, Dengjel J, Neundorf I, Bano D, Poepsel S, Riemer J (2025) Interaction with AK2A links AIFM1 to cellular energy metabolism. Molecular Cell 85(13):2550-2566.e6
2. Peker E, Weiss K, Song J, Zarges C, Gerlich S, Boehm V, Trifunovic A, Langer T, Gehring NH, Becker T, Riemer J (2023) A two-step mitochondrial import pathway couples the disulfide relay with matrix complex I biogenesis. Journal of Cell Biology 222 (7), e202210019
3. Hoehne MN, Jacobs LJHC, Lapacz KJ, Calabrese G, Murschall LM, Marker T, Kaul H, Trifunovic A, Morgan B, Fricker M, Belousov VV, Riemer J (2022). Spatial and temporal control of mitochondrial H₂O₂ release in intact human cells. EMBO J41(7):e109169
4. Salscheider SL, Gerlich S, Cabrera‐Orefice A, Peker E, Rothemann RA, Murschall LM, Finger Y, Szczepanowska K, Ahmadi ZA, Guerrero‐Castillo S, Erdogan A, Becker M, Ali M, Habich M, Petrungaro C, Burdina N, Schwarz G, Klußmann M, Neundorf I, Stroud DA, Ryan MT, Trifunovic A, Brandt U, Riemer J (2022) AIFM1 is a component of the mitochondrial disulfide relay that drives complex I assembly through efficient import of NDUFS5. EMBO J 41 (17), e110784
5. Finger Y, Habich M, Gerlich S, Urbanczyk S, van de Logt E, Koch J, Schu L, Lapacz KJ, Ali M, Petrungaro C, Salscheider SL, Pichlo C, Baumann U, Mielenz D, Dengjel J, Brachvogel B, Hofmann K, Riemer J (2020) Regulated cytosolic processing of mitochondrial precursors by DPP9 controls mitochondrial protein import. EMBO J, 20:e103889