GDF15 was initially isolated as a transcript produced by activated macrophages, which encoded a protein with some homology to the transforming growth factor beta (TGFβ) superfamily [27]. Increased circulating GDF15 levels have been observed following physical activity and during pregnancy with increases as much as 40-fold in the latter [18, 28]. Elevations in GDF15 are not limited to these physiological states and in the 20 years since its discovery, increases in the peptide have been reported in a variety of pathological conditions including aging, cardiac failure, chronic kidney disease, mitochondrial disease and malignancy [16, 17]. However, it was the identification of GFRAL, a transmembrane receptor localised to the hindbrain, as the putative target for GDF15 and mediator of its weight lowering effects in rodents that framed GDF15 as a potential anti-obesity therapy [13,14,15].

As the study of the weight lowering effects of GDF15 continues it has been intriguing to see that GDF15 is not regulated by the nutritional stimuli known to influence other hormones implicit in energy homeostasis, this suggests that GDF15 has not evolved for this biological purpose [16, 29]. The spectrum of conditions reported to be associated with elevations in GDF15 share a common thread of cellular stress, raising the possibility that GDF15 may have evolved as part of a stress response signal that may incidentally influence energy balance. Insights into the role of GDF15 as a signal of cellular stress has been aided by the study of disorders of mitochondrial function. Recent work from Chung et al. illustrate that in mice with a muscle specific knockout for crif1, a protein integral to the mitoribosomal subunit 39S, the ensuing mitochondrial unfolded protein response mediates increased GDF15 expression in a process that is dependent on the activation of the CHOP, a stress induced pro-apoptotic transcription factor [30]. Similarly, in vitro, GDF15 expression is responsive to activation of the integrated stress response (IRS), an adaptive response to stressful stimulus in eukaryotic cells [29, 31]. Markedly increased circulating GDF15 values have now been reported in a variety of inherited mitochondrial diseases [32,33,34,35]. The apparent symptom overlap between patients affected by ME/CFS and mitochondrial disorders has generated discussion into the possibility of a shared pathophysiology between the respective conditions [36]. Considering GDF15’s potential as a novel marker of mitochondrial dysfunction, we hypothesised that it may represent a biomarker of mitochondrial stress in ME/CFS [37].

In our analysis, we included both healthy control subjects in addition to a cohort of patients diagnosed with multiple sclerosis. The observation that GDF15 measurements do not significantly change over longitudinal follow-up of patients affected with ME/CFS reassures us of its value as a potential biomarker. Interestingly in the subset of participants with MS we saw that GDF15 increased significantly from baseline assessment. GDF15 levels are significantly increased in a cohort of ME/CFS patients categorised as having severe disease when compared to a healthy control group. The observation that GDF15 levels associate with severe rather than mild/moderate disease is indicative of a relationship between ME/CFS disease severity and GDF15. These findings mirror reports from the study of primary mitochondrial disorders with Yatsuga et al. [34] demonstrating a positive correlation between GDF15 and both the Japanese Mitochondrial Disease Rating Scale and the Newcastle Mitochondrial Scale for Adults, which represent semi-quantitative clinical rating scales. In the case of our ME/CFS study cohort the fatigue severity scale correlated with GDF15 levels, these findings lend further support for a role for GDF15 as a marker of symptom severity in ME/CFS.

However, it is important to note that in contrast to the levels observed in primary disorders of mitochondrial function, the mean GDF15 levels measured in our ME/CFS cohort are many fold lower [33, 35]. This is not surprising given the widespread mitochondrial dysfunction observed in disorders such as Leigh’s syndrome, but it suggests that significant impairment of mitochondrial function may not be as prominent a feature of ME/CFS. Certainly, enrichment for pathogenic mutations in mitochondrial DNA has not been seen among patients affected by ME/CFS [38]. However, there are a number of conflicting reports on the relationship between mitochondrial dysfunction and disease severity in ME/CFS [12]. We expect that the emergence of GDF15 as a biomarker of mitochondrial dysfunction will support ongoing efforts to study this relationship.

In ME/CFS it is not clear what tissue or tissues may be contributing to the elevated levels GDF15 observed in severe disease. We know that in humans, GDF15 is expressed in a wide range of tissues with highest expression in the liver, kidney, prostate, colon, adipose tissue and placenta [39]. Interestingly, GDF15 or MIC-1 was initially cloned from a macrophage cell line. However, Sweetman et al. [40] did not report a significant change in GDF15 transcription in PBMCs from ME/CFS patients. We have seen in primary mitochondrial disorders associated with overt myopathy that GDF15 expression is massively upregulated in skeletal muscle and this is associated with an increase in circulating levels [32]. However, there are no reports of GDF15 expression in muscle or other tissues of humans with ME/CFS. Further study is required to determine the source of increased circulating GDF15 observed in a subset of ME/CFS patients.

Thus far we have considered GDF15 as a potential biomarker in ME/CFS rather than a contributing factor to the symptomatology observed in this cohort. Fatigue is frequently reported in the conditions associated with increased GDF15, although the relationship between fatigue in these disease states and GDF15 has not been formally studied in humans. Reduced locomotor activity has been reported in transgenic mice that over-express GDF15 and wild-type animals exposed to pharmacological doses of the peptide [19, 20]. The reason for the decreased activity has not been elucidated, however, it is speculated that this may be reflective of reduced food seeking behaviour. In humans, understanding whether GDF15 contributes to the symptoms of fatigue or is simply a circulating marker of the underlying disease process will necessitate further study. However, in time, both the administration of GDF15 to humans and/or the pharmacological manipulation of the GDF15-GFRAL axis in specific diseases that increase GDF15 could provide valuable insight on the contribution of GDF15 to symptoms of fatigue. Certainly, in ME/CFS the biological relevance of the circulating levels at which GDF15 we have observed is unclear.