Tanaka 2015 Abstract MiP2015
|GDF15 is a novel biomarker to evaluate efficacy of pyruvate therapy for mitochondrial diseases.|
We proposed that the addition of pyruvate would facilitate oxidation of NADH to NAD+ via the lactate dehydrogenase reaction, which would restore ATP production by the glycolytic pathway even under defective respiratory conditions . Indeed, positive effects of sodium pyruvate on clinical manifestations of mitochondrial diseases have been reported . However, useful biomarkers for evaluating the therapeutic efficacy of pyruvate remain to be developed.
In our earlier study , we found that exposure to excessive sodium lactate significantly increases the intracellular L/P and NADH/NAD+ ratios in cybrid cells harboring the MELAS mutation (m.3243A>G), which implies worsening of lactic acidosis and NAD+ shortage. On the other hand, we found that treatment with sodium pyruvate facilitates the ATP production and improves the energy status, as indicated by a decrease in the L/P ratio and retention of the NADH/NAD+ ratio. Taken together, we considered that these experimental conditions would be ideal for identifying biomarker candidate genes, whose expression levels reflect the intracellular energy deficiency and the effect of pyruvate on energy metabolism.
In the present study, we performed a global gene expression analysis of cybrid cells with the MELAS mutation (m.3243A>G: 2SD cells) and control cybrid cells (2SA cells) treated or not with lactate or pyruvate. We identified several biomarker candidate genes, among which we focused on growth differentiation factor 15 (GDF15). The level of GDF15 in the conditioned medium was significantly higher in 2SD cells than in 2SA cells, which level was further increased by lactate but was not affected by pyruvate in 2SD cells. We also demonstrated that the concentration of GDF15 in the serum was markedly elevated in patients with mitochondrial diseases compared with that in those with other pediatric diseases.
Thus, we identified GDF15 as a novel serum marker for the diagnosis of mitochondrial diseases and possibly for monitoring the disease status and progression and for evaluating the therapeutic efficacy of pyruvate.
• O2k-Network Lab: JP Tokyo Tanaka M
Labels: MiParea: Respiration, mtDNA;mt-genetics, nDNA;cell genetics, Patients
Tissue;cell: Other cell lines
Event: A3, Oral MiP2015, JP
1-Dept Genomics Longevity Health, Tokyo Metropolitan Inst Gerontol (TMIG); 2-Dept Mechanism Aging, TMIG; 3-Health Support Center, Toyohashi Univ Technol; 4-Dept Pediatrics Child Health, Kurume Univ Sch Med, Japan. - [email protected]
Figure 1. Measurement of the GDF15 concentration in the serum of patients. The serum GDF15 concentrations in 17 patients with mitochondrial diseases as well as those in 13 patients with other pediatric diseases were determined by ELISA.
References and acknowledgements
- Tanaka M, Nishigaki Y, Fuku N, Ibi T, Sahashi K, Koga Y (2007) Therapeutic potential of pyruvate therapy for mitochondrial diseases. Mitochondrion 7:399-403.
- Koga Y, Povalko N, Katayama K, Kakimoto N, Matsuishi T, Naito E, Tanaka M (2012) Beneficial effect of pyruvate therapy on Leigh syndrome due to a novel mutation in PDH E1α gene. Brain Dev 34:87-91.
- Kami K, Fujita Y, Igarashi S, Koike S, Sugawara S, Ikeda S, Sato N, Ito M, Tanaka M, Tomita M, Soga T (2012) Metabolomic profiling rationalized pyruvate efficacy in cybrid cells harboring MELAS mitochondrial DNA mutations. Mitochondrion 12:644–53.
- Fujita Y, Ito M, Kojima T, Yatsuga S, Koga Y, Tanaka M (2015) GDF15 is a novel biomarker to evaluate efficacy of pyruvate therapy for mitochondrial diseases. Mitochondrion 20:34-42.