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Iyer 2022 Abstract Bioblast

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Iyer Shilpa
Not presented 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. In:

Link: Bioblast 2022: BEC Inaugural Conference

Iyer Shilpa, Bakare A, Dean J, Chen Qun, Thorat V, Huang Y, LaFramboise T, Rao RR, Lesnefsky Edward J (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 [1,2]. Other symptoms are widespread tissue malfunction in brain stem and muscle in LS patients. We hypothesize that altered bioenergetic function caused by mitochondrial genome mutations in the electron transfer 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 the mitochondrial bioenergetics health index (mtBHI) and glycolytic bioenergetics health index (glycoBHI) for measuring overall 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). The mtBHI was based on four key aspects of mitochondrial respiration: ET capacity minus ROUTINE respiration (E-R), net ROUTINE respiration (R-L), residual oxygen consumption Rox after inhibition by rotenone and antimycin A (ROX state), and LEAK respiration L. The glycoBHI was based on four key aspects of cellular proton efflux rate linked to glycolysis [3].

Our results indicated that (1) high heteroplasmy was detected in disease lines affecting ATP synthase and low heteroplasmy was detected in disease lines affecting NADH dehydrogenase; (2) levels of defective enzyme activities of the ETS correlated with the percentage of pathogenic mtDNA; (3) mitochondrial respiration was disrupted in diseased lines with variable E-R; (4) mitochondrial ATP synthesis rate was decreased while glycolytic ATP synthesis rate was 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 because the cells had switched ‘on’ the glycolytic pathway. GlycoBHI was significantly increased in all cell lines compared to control BJ-FB and was indeed sensitive to mitochondrial dysfunction. We also computed the ‘composite BHI ratio’ (OXPHOS/Glycolysis) by dividing mtBHI/glycoBHI values because the cell lines were utilizing both OXPHOS (although highly defective) and glycolysis pathways to maintain the energy requirements in the individual cell line.

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) reprogrammed from these patient fibroblast cells, followed by bioenergetic analyses in differentiated neurons and muscle cells derived from 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.

  1. Bakare AB, Lesnefsky EJ, Iyer S (2021) Leigh Syndrome: a tale of two genomes.
  2. 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.
  3. 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.

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


Iyer S1, Bakare A1, Dean J2, Chen Q3, Thorat V4, Huang Y4, LaFramboise T4, Rao RR5, Lesnefsky EJ2,6
  1. Dept of Biological Sciences, J. William Fulbright College of Arts and Sciences, University of Arkansas, Fayetteville, Arkansas, USA - [email protected]
  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


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

Organism: Human  Tissue;cell: Fibroblast