Mitochondrial complex II and V activity is enhanced in pediatric acute myeloid leukemia.

Abstract

Background: Mitochondrial bioenergetic alterations are commonly observed metabolic adaptation in malignancies including acute myeloid leukemia (AML). Mitochondrial DNA alterations are well known in pediatric AML with possible prognostic significance; however, mitochondrial complex activity and its impact on disease outcome have not been previously explored. The aim of this study was to evaluate the mitochondrial complex II and complex V activity and its prognostic significance in pediatric AML patients.

Methods: Consecutive 82 de novo pediatric (≤18 years) patients with AML were included in the study along with age and sex matched controls. Bone marrow mononuclear cells were isolated from baseline bone marrow samples from all patients and controls. DNA, RNA and proteins were extracted and relative expression of mitochondrial biogenesis genes TFAM, POLG, POLRMT were estimated along with mitochondrial DNA copy number. The mitochondrial complex II and V enzymes were immunocaptured and their activity was measured by substrate specific absorbance change by kinetic ELISA. The mitochondrial complex II and V activity was compared with controls and their association with clinico-pathological features and survival outcome were analysed. Complex activity was also correlated with relative expression of biogenesis genes.

Results: The activity of mitochondrial complex II and V were found to be significantly enhanced (P = 0.010 and P = 0.0013 respectively) in pediatric AML patients compared to controls. The activity of mitochondrial complex II and V showed significant positive correlation with relative gene expression of mitochondrial biogenesis genes TFAM (P = 0.001 and P = 0.016 respectively) and POLG (P = 0.005 and P = 0.006 respectively). Neither of the two complex activities showed any significant association with baseline disease demographics or any clinico-pathological feature. Furthermore, the complex II and V activity did not show any impact on event free survival (P = 0.25 and P = 0.24 respectively) and overall survival (P = 0.14 and P = 0.17 respectively) in our cohort.

Conclusion: The activity of both mitochondrial complex II and V are significantly elevated in bone marrow mononuclear cells of children with AML compared to controls. The enhanced activity may be related to upregulation of mitochondrial biogenesis genes TFAM and POLG. The enhanced activity of either of the complexes did not impact disease biology or survival outcomes in pediatric AML.