Iyer 2022 Abstract Bioblast

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Iyer Shilpa
Iyer Shilpa, Bakare A, Dean J, Chen Q, Thorat V, Huang Y, LaFramboise T, Rao RR, Lesnefsky EJ (2022) Bioenergetics health index ratio in Leigh Syndrome patient fibroblasts as a measure of disease severity. Bioblast 2022: BEC Inaugural Conference.

Link: Bioblast 2022: BEC Inaugural Conference

Iyer S, Bakare A, Dean J, Chen Q, Thorat V, Huang Y, LaFramboise T, Rao RR, Lesnefsky EJ (2022)

Event: Bioblast 2022

Leigh Syndrome (LS), is a severe neuro-metabolic disorder and has no current cure or adequate cellular models to understand the rapid fatality associated with the disease. Other symptoms are widespread tissue malfunction in brain stem and muscle in LS patients. We hypothesize that altered bioenergertic function caused by mitochondrial genome mutations in the electron transport system (ETS) may lead to rapid fatality in LS. 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 ATP synthase or Complex I (T10158C, T12706C). Our results indicated that (a) high heteroplasmy was detected in disease lines affecting ATP synthase and low heteroplasmy was detected in disease lines affecting NADH dehydrogenase; (b) levels of defective enzyme activities of the ETS correlated with the percentage of pathogenic mtDNA; (c) mitochondrial respiration was disrupted in diseased lines with variable spare respiratory capacity (SRC) (d) mitochondrial ATP synthesis rate is decreased while glycolytic ATP synthesis rate is elevated in diseased cell lines. Based on the overall analysis of the five diseased patient-specific fibroblasts, the ‘glycoBHI’ emerged as a sensitive indicator of mitochondrial defects as the cells had switched ‘on’ the glycolytic pathway. GlycoBHI was significantly increased in all the cell lines compared to control BJ-FB and was indeed sensitive to mitochondrial dysfunction. We also computed the ‘composite BHI ratio’ OXPHOS/glycolysis because the cell lines were utilizing both OXPHOS (although highly defective) and glycolysis pathways to maintain the energy requirements in the individual cell line. Two important parameters associated with the composite BHI ratio were basal glycolysis (PER), which was a measure of mitochondrial defect, and SRC, which was an indicator of the cell’s capacity to adapt to the defect. Overall, these results suggest that as long as the precise mechanism of LS has not been elucidated, a multi-pronged approach that takes into consideration the specific pathogenic mtDNA variant, along with a composite BHI ratio, can aid in better diagnosis and understanding the factors influencing disease severity and rapid fatality in LS. Future experiments will determine whether mitochondrial morphology depend on mtDNA mutation load and whether they influence bioenergetics within a cell. Our ongoing studies are focused on evaluating mutation burden in human induced pluripotent stem cells (hiPSCs), followed by bioenergetic analyses in differentiated neurons and muscle cells from LS-hiPSCs. Results from these studies will address the knowledge gaps that exist in the understanding of relationships among mtDNA mutations, morphology, function, and cell fate that may ultimately contribute to devastating mitochondrial disorders.

Keywords: Mitochondrial disorders, Leigh syndrome, Glycolysis, Mitochondrial respiration, Bioenergetics health index Bioblast editor: Plangger M O2k-Network Lab: US AR Fayetteville Iyer S


Iyer S(1), Bakare A(1), Dean J(2), Chen Q(3), Thorat V(4), Huang Y(4), LaFramboise T(4), Rao RR(5), Lesnefsky EJ(2)
  1. Dept of Biological Sciences, J. William Fulbright College of Arts and Sciences, University of Arkansas, Fayetteville, Arkansas, USA
  2. Cardiology Section Medical Service, McGuire Veterans Affairs Medical Center, Richmond, Virginia, USA
  3. Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
  4. Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
  5. Department of Biomedical Engineering, College of Engineering, University of Arkansas, Fayetteville, Arkansas, USA
  6. Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia, USA. -si012@uark.edu


  1. Grace HE, Galdun P, Lesnefsky EJ, West FD, Iyer S (2019) mRNA reprogramming of T8993G Leigh's Syndrome fibroblast cells to create induced pluripotent stem cell models for mitochondrial disorders. Stem Cells Development 28:846-59. 10.1089/scd.2019.0045
  2. Bakare AB, Dean J, Chen Q, Thorat V, Huang Y, LaFramboise T, Lesnefsky EJ, Iyer S (2021) Evaluating the bioenergetics health index ratio in Leigh Syndrome fibroblasts to understand disease severity. Int J Mol Sci 22:10344. 10.3390/ijms221910344
  3. Bakare AB, Lesnefsky EJ, Iyer S (2021) Leigh Syndrome: a tale of two genomes. Frontiers Physiol 12:693734. 10.3389/fphys.2021.693734


Labels: MiParea: mtDNA;mt-genetics, Patients  Pathology: Neurodegenerative 

Organism: Human  Tissue;cell: Fibroblast