Evaluating the Bioenergetics Health Index Ratio in Leigh Syndrome Fibroblasts to Understand Disease Severity

Several pediatric mitochondrial disorders, including Leigh syndrome (LS), impact mitochondrial (mt) genetics, development, and metabolism, leading to complex pathologies and energy failure. The extent to which pathogenic mtDNA variants regulate disease severity in LS is currently not well understood. To better understand this relationship, we computed a glycolytic bioenergetics health index (BHI) for measuring mitochondrial dysfunction in LS patient fibroblast cells harboring varying percentages of pathogenic mutant mtDNA (T8993G, T9185C) exhibiting deficiency in complex V or complex I (T10158C, T12706C). A high percentage (> 90%) of pathogenic mtDNA in cells affecting complex V and a low percentage (< 39%) of pathogenic mtDNA in cells affecting complex I was quantified. Levels of defective enzyme activities of the electron transport chain correlated with the percentage of pathogenic mtDNA. Subsequent bioenergetics assays showed cell lines relied on both OXPHOS and glycolysis for meeting energy requirements. Results suggest that whereas the precise mechanism of LS has not been elucidated, a multi-pronged approach taking into consideration the specific pathogenic mtDNA variant, glycolytic BHI, and the composite BHI (average ratio of oxphos to glycolysis) can aid in better understanding the factors influencing disease severity in LS.

Automated summary

The study investigated mitochondrial dysfunction in fibroblast cells of Leigh syndrome patients with different percentages of pathogenic mutant mtDNA using a glycolytic bioenergetics health index (BHI). It was found that the percentage of pathogenic mtDNA correlated with defective enzyme activities in the electron transport chain, and cell lines relied on both OXPHOS and glycolysis for meeting energy requirements. The study suggests that a multi-pronged approach considering specific pathogenic mtDNA variants, glycolytic BHI, and the composite BHI can aid in better understanding the factors influencing disease severity in Leigh syndrome.