1. Research Background:

Our metabolism has to adapt constantly to changing environmental conditions, including illness, physical activity or dietary habits. As we grow older, our cells are less capable of adjusting to environmental changes and metabolic stress, leading to disruptions in energy balance, increased risk of obesity, and other age-associated metabolic disorders. Exercise training remodels our metabolism and can prevent and ameliorate many age-associated metabolic disorders, thereby extending health- and life-span. Many of the beneficial effects of exercise training in skeletal muscle seemingly involve a remodeling of the mitochondrial compartment. Mitochondria harbor the enzymatic machinery to control many molecular pathways important to ensure functioning of metabolic networks and maintain energy homeostasis. Intact mitochondrial compartments are key to enable our metabolism to adapt to changing environmental conditions. As we age, physical activity and mitochondrial function decline, disrupting energy homeostasis and causing age-associated metabolic diseases. However, our knowledge about the underlying molecular mechanisms maintaining mitochondrial function in response to exercise or leading tomitochondrial dysfunction with age remains far from complete. Over the last years it became increasingly clear thatmitochondrial metabolites play an important role during these processes by not only supplying substrates for biological processes but also by serving as signaling molecules. Additionally, the regulation of metabolite compartmentalization by specific transport proteins in the inner mitochondrial membrane represent an important step in maintaining energy homeostasis.

2. Research questions addressed by the group:

The overall aim of our research group is to identify unknown molecular mechanisms controlling mitochondrial function, thereby maintaining energy homeostasis and protecting against age- related decline. Additionally, we are interested in identifying the molecules and molecular mechanisms mediating mitochondrial improvements in response to exercise training in different tissues and explore their therapeutic potential. To this end, we study mitochondrial metabolism in response to exercise and during age-associated metabolic diseases in different cell types in vivo and in cultured cells. We are particularly interested in the regulation of metabolite compartmentalization and the role of metabolites in regulating protein function inside mitochondria.

3. Possible projects:

Specific questions we are planning to address with our research:

1. How is mitochondrial metabolism remodeled in different cell types in response to exercise training?
2. How do different exercise regimens affect mitochondrial metabolism in different cell types?
3. What are the underlying molecular mechanisms of exercise adaptation relevant for the ageing process?
4. Are those mechanisms of equal importance in males and females?

4. Applied Methods and model organisms:

• Model organisms: Transgenic mouse models and mammalian cell culture
• Methods: Mouse phenotyping incl. different exercise regimens and indirect calorimetry, genetics, molecular biology, organellar-IPs, mass spectrometry, recombinant protein work, biochemistry

5. Desirable skills and qualifications:

We seek an enthusiastic and creative PhD student who has a strong interest in molecular metabolism andwants to join an international and collaborative team. While the skills in the above-mentioned methods can be acquired as part of the PhD, prior knowledge in mouse handling, mitochondrial biology or recombinant protein work will be advantageous.

6. References and key publications:

1. Chow, L. S. et al. Exerkines in health, resilience and disease. Nat Rev Endocrinol, 2022.
2. Reddy, A. et al. pH-Gated succinate secretion regulates muscle remodeling in response to exercise. Cell, 2020.
3. Bar-Peled & Kory. Principles and functions of metabolic compartmentalization. Nat. Metab., 2022
4. Bayraktar, E. C. et al. MITO-Tag Mice enable rapid isolation and multimodal profiling of mitochondriafrom specific cell types in vivo. Proc Natl Acad Sci U S A, 2019.
5. Sprenger, H.G. et al. Ergothioneine boosts mitochondrial respiration and exercise performance via direct activation of MPST. bioRxiv, 2024