Mitohormesis, Mitokines and Healthy Aging

Contact: Prof. Dr. Susanne Klaus

Funding: Deutsche Forschungsgemeinschaft (DFG)

Fig. 1: Mitochondria are important organelles for cellular homeostasis and metabolic health.

Mitochondria, the crucial organelles for cellular energy generation and biosynthetic pathways, are responsible for about 90 % of total oxygen consumption in mammalian cells, 80 % of which is coupled to ATP synthesis. They are essential for normal cell function and can rapidly adapt to different cellular metabolic requirements. As an important component of cellular homeostasis, mitochondria are also of major importance for organismal health. Mitochondrial dysfunction is a driver of various diseases and also implicated in the aging process (Fig. 1).

However, mild mitochondrial dysfunction can trigger adaptations that, paradoxically, can even improve cellular and organismal health. According to the concept of mitohormesis, perturbations of mitochondrial function by diverse stressors can lead to alterations in cytosolic and nuclear signaling which induce cytoprotective pathways resulting in an increased stress resistance. These mitohormesis pathways can act in a cell-autonomous fashion to preserve cellular function and survival but they can also affect and improve systemic metabolism potentially leading to an improvement of health and even an increased lifespan.

In recent years we could demonstrate this mitohormesis effect in a mouse model of healthy aging. These UCP1-mice are characterized by an ectopic expression of the mitochondrial uncoupling protein UCP1 in skeletal muscle. Despite a reduced muscle mass and strength, these mice show a healthy metabolic phenotype and an increased longevity suggesting a role of mitochondrial uncoupling in ageing and longevity (Klaus & Ost. Exp. Geront. 2020).

Beside muscle specific adaptations, UCP1 mice also display a number of beneficial metabolic adaptions in other organs and cell types pointing to a cross talk between muscle and the whole organism, possibly by so called mitokines. These are defined as molecules such as peptides or cytokines that are released by cells in response to mitochondrial stress, in this case muscle cells, and which then act on other cells or tissues. In our mouse model we could identify FGF21 (fibroblast growth factor 21) and GDF15 (growth diffenciation factor 15) as stress induced mitokines of the skeletal muscle, so called myokines. (Keipert et al. Am. J. Physiol. Endocrinol. Metab. 2014; Ost et al. EMBO Rep. 2020).

Fig. 2: Activation of the GDF15-GFRAL axis by skeletal muscle mitochondrial stress induces hypothalamic CRH and drives changes in feeding and anxiety behavior AP: area postrema; CRH: corticotropin releasing hormone; CRHR1: CRH receptor 1; GFRAL: GDNF receptor alpha-like; HTH: Hypothalamus; NTS: nucleus solitary tract.

Both, FGF21 und GDF15 are similarly induced by mitochondrial dysfunction and cellular stress but seem to have different functions in energy metabolism (Klaus et al. Cell. Mol. Life Sci. 2021). Since FGF21 proved to be dispensable for most of the metabolic adaptations of UCP1 mice we have recently focused on GDF15 whose metabolic role is receiving considerable research attention since the recent identification of GFRAL (GDNF receptor alpha-like) as its unique receptor which is exclusively expressed in the hindbrain. Until now, most mechanistic studies on GDF15 rely on pharmacological interventions using exogenous GDF15, but little is known about its mode of action when induced both chronically and endogenously. Using the UCP1 mouse model we showed a circadian oscillation of muscle-derived GDF15 to promote a daytime-restricted, GDF15 dependent anorexia without signs of visceral malaise, the later contrary to findings using recombinant GDF15. Activation of the GDF15-GFRAL pathway resulted in increased anxiety-like behavior and hypothalamic corticotropin releasing hormone (CRH) induction, without further activation of the hypothalamic-pituitary-adrenal (HPA) axis.

This, as well as the daytime-restricted anorexia and improved metabolic phenotype was completely abolished by GFRAL ablation. Furthermore, we could demonstrate that stress-induced GDF15-GFRAL signaling is required for hypothalamic CRH induction to control diurnal food intake in a CRH-receptor 1 (CRHR1)-dependent manner. We thus uncovered for the first time a molecular target of the GDF15-GFRAL axis that links anxiety-related and anorectic behavior as downstream effects of the chronic activation of this pathway by mitochondrial stress (Ost et al. EMBO Rep. 2020; Igual et al. BiorXiv, 2021).