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Identification of GDF15 as a diagnostic marker for mitochondrial diseases

Yasunori Fujita, Ph.D.

Researcher ( Research Team for Mechanism of Aging )

Mitochondrial diseases caused by mitochondrial or nuclear DNA mutations are intractable. A variety of symptoms are caused by impaired energy metabolism due to mitochondrial dysfunction. The development of a novel biomarker for diagnosis of these diseases and for evaluation of clinical severity and therapeutic efficacy is necessary. We previously demonstrated that treatment with lactate exacerbated the energy deficiency of 2SD cybrid cells harboring the MELAS-causing m.3243A>G mutation, but that treatment with pyruvate improved the intracellular energy status. To identify biomarkers that reflect intracellular energy status, we performed a global gene expression analysis of 2SD cybrid cells and 2SA control cybrid cells treated with either lactate or pyruvate. We selected genes that were significantly up-regulated by lactate but not by pyruvate in 2SD cells. We then selected 23 genes whose products were annotated as being in the extracellular space. Of these genes, the expression level of growth differentiation factor 15 (GDF15) was highly increased in 2SD cells treated with lactate. The level of GDF15 secreted from 2SD cells was significantly higher than that from 2SA cells. Furthermore, GDF15 secretion from 2SD cells was increased by lactate, suggesting that the intracellular energy status could be monitored by analysis of GDF15. Finally, we found that the serum GDF15 concentration was significantly higher in patients with mitochondrial diseases than in those with other pediatric diseases. Our results suggest that GDF15 could be a useful marker for diagnosing mitochondrial diseases and possibly for monitoring intracellular energy status.

1. Fujita Y, Ito M, Kojima T, Yatsuga S, Koga Y, Tanaka M. GDF15 is a novel biomarker to evaluate efficacy of pyruvate therapy for mitochondrial diseases. Mitochondrion. 20: 34-42, 2015
2. Kami K, Fujita Y, Igarashi S, Koike S, Sugawara S, Ikeda S, Sato N, Ito M, Tanaka M, Tomita M, Soga T. Metabolomic profiling rationalized pyruvate efficacy in cybrid cells harboring MELAS mitochondrial DNA mutations. Mitochondrion 12: 644-53, 2012.