Mitohormesis, Mitokines and Healthy Aging
Contact: Prof. Dr. Susanne Klaus
Funding: Deutsche Forschungsgemeinschaft (DFG)
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. 2.1.).
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 (Klaus et al., 2005; Katterle et al., 2008, Neschen et al., 2008; Keipert et al., 2011; Ost et al., 2015). When fed a high fat diet UCP1 mice even showed an increased longevity associated with a reprogramming of muscle metabolism. This is characterized by an increased protein and amino acid turnover with an increased serine, one carbon, glycine synthesis and trans-sulfuration pathway. Thereby muscle cells increase their NADPH production and glutathione metabolism as an adaptive mitohormetic response and defense against oxidative stress. We could thus identify a compensatory stress signaling network to maintain cellular function during mitochondrial dysfunction. (Ost et al., 2015).
Beside these cell autonomous 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., 2014; Ost et al., 2020).
Both, FGF21 und GDF15 are similarly induced by mitochondrial dysfunction and cellular stress but seem to have different functions in energy metabolism (Klaus & Ost, 2020). FGF21, normally secreted by the liver, affects glucose and liver metabolism by both peripheral and central mechanisms. GDF15 on the other hand acts only centrally, according to our current state of knowledge, mainly by a suppression of food intake. A specific receptor for GDF15 has so far only been found in certain areas of the brain stem. Interestingly, ablation of FGF21 had little effects on the metabolic phenotype of UCP1 mice. Only the induction of brown adipocytes in typical white depots (browning) and the reduction of circulating triglycerides and cholesterol was dependent on FGF21 (Ost et al., 2016). Contrary to that, ablation of GDF15 had much larger and long-lasting effects on the metabolic phenotype of UCP1 mice. UCP1 mice with ablation of GDF15 (obtained by crossing with GDF15 knock-out mice) showed a progressive increase in adiposity and insulin resistance even on a regular low-fat diet. This effect could be explained by a diurnal anorectic effect of GDF15. Muscle secretion of GDF15 was higher during day time than during night time (the normal activity period of nocturnal mice). This led to a complete suppression of food intake during day time but not during night time (Ost et al., 2020) This diurnal anorectic effect is apparently sufficient to explain the beneficial metabolic adaptations of UCP1 mice (Fig. 2.2.).
Currently we are further investigating the role of FGF21 and GDF15 in energy metabolism and metabolic regulation. We will explore the possibility of an oral supply of FGF21 expressed in plants (in planta bioencapsulation) with respect to liver specific beneficial effects on lipid metabolism. Furthermore, we aim to investigate in more detail the central anorectic and behavioral action of GDF15 and the role of its brain stem restricted receptor. In addition, we will investigate a possible local role of GDF15 in muscle regeneration and exercise adaptation since previously we have observed alterations in muscle cellular exercise adaptations in GDF15 knock out mice (Igual et al., 2019).