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Published on: June 30, 2023
Reduced Mitochondrial Function in Human Huntington Disease Lymphoblasts is Not Due to Alterations in Cardiolipin
Edgard M Mejia1, Sarah Chau2, Genevieve C Sparagna2
1Department of Pharmacology and Therapeutics, Faculty of Health Sciences, University of Manitoba, 501C-715 McDermot Avenue, Winnipeg, MB, R3E 3P4, Canada.
Insights
Huntington's Disease (HD) lymphoblasts show impaired mitochondrial energy metabolism, including reduced respiration and glycolysis. However, this dysfunction is not linked to changes in cardiolipin (Ptd2Gro) metabolism.
Area of Science:
- Biochemistry
- Neuroscience
- Genetics
Background:
- Huntington's Disease (HD) is an inherited neurodegenerative disorder characterized by CAG repeat expansion in the HTT gene.
- Mitochondrial dysfunction is a hallmark of HD, affecting neuronal and peripheral tissues.
- Cardiolipin (Ptd2Gro) is a critical mitochondrial phospholipid essential for maintaining energy production.
Purpose of the Study:
- To investigate the role of cardiolipin (Ptd2Gro) metabolism in the mitochondrial dysfunction observed in Huntington's Disease.
- To assess energy metabolism parameters in lymphoblasts from HD patients.
Main Methods:
- Comparison of mitochondrial respiration, ATP coupling, and glycolysis rates between HD lymphoblasts and controls.
- Analysis of mitochondrial supercomplex formation and Complex I activity.
- Assessment of cardiolipin (Ptd2Gro) synthesis, remodeling, and molecular species composition.
Main Results:
- HD lymphoblasts exhibited significantly diminished mitochondrial basal respiration, spare respiratory capacity, ATP coupling efficiency, and glycolysis rates.
- Mitochondrial supercomplexes and Complex I activity within supercomplexes were unaltered in HD lymphoblasts.
- In vitro Complex I enzyme activity was reduced in HD lymphoblasts, while cardiolipin (Ptd2Gro) levels and metabolism remained unchanged.
Conclusions:
- Huntington's Disease lymphoblasts display impaired mitochondrial energy metabolism independent of alterations in cardiolipin (Ptd2Gro) metabolism.
- HD lymphoblasts serve as a valuable model for studying energy metabolism defects not associated with cardiolipin pathway disruptions.
Abstract:
Huntington's Disease (HD) is an autosomal dominant disease that occurs as a result of expansion of the trinucleotide repeat CAG (glutamine) on the HTT gene. HD patients exhibit various forms of mitochondrial dysfunction within neurons and peripheral tissues. Cardiolipin (Ptd2Gro) is a polyglycerophospholipid found exclusively in mitochondria and is important for maintaining mitochondrial function. We examined if altered Ptd2Gro metabolism was involved in the mitochondrial dysfunction associated with HD. Mitochondrial basal respiration, spare respiratory capacity, ATP coupling efficiency and rate of glycolysis were markedly diminished in Epstein-Barr virus transformed HD lymphoblasts compared to controls (CTRL). Mitochondrial supercomplex formation and Complex I activity within these supercomplexes did not vary between HD patients with different length of CAG repeats and appeared unaltered compared to CTRL. In contrast, in vitro Complex I enzyme activity in mitochondrial enriched samples was reduced in HD lymphoblasts compared to CTRL. The total cellular pool size of Ptd2Gro and its synthesis/remodeling from [(3)H]acetate/[(14)C]oleate were unaltered in HD lymphoblasts compared to CTRL. In addition, the molecular species of Ptd2Gro were essentially unaltered in HD lymphoblasts compared to CTRL. We conclude that compared to CTRL lymphoblasts, HD lymphoblasts display impaired mitochondrial basal respiration, spare respiratory capacity, ATP coupling efficiency and rate of glycolysis with any pathological CAG repeat length, but this is not due to alterations in Ptd2Gro metabolism. We suggest that HD patient lymphoblasts may be a useful model to study defective energy metabolism that does not involve alterations in Ptd2Gro metabolism.
