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Updated: Aug 18, 2026
Assessment of Open Probability of the Mitochondrial Permeability Transition Pore in the Setting of Coenzyme Q Excess
Published on: June 1, 2022
Ca2+-induced permeability transition in human lymphoblastoid cell mitochondria from normal and Huntington's disease
Alexander V Panov1, Serena Lund, J Timothy Greenamyre
1Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA 30322, USA. apanov@emory.edu
Insights
Mutated huntingtin in Huntington's disease (HD) affects mitochondria in peripheral blood cells. This protein impairs mitochondrial function by promoting low proton conductance, not by directly causing permeability transition.
Area of Science:
- Mitochondrial Biology
- Neurodegenerative Diseases
- Cellular Physiology
Background:
- Huntington's disease (HD) is caused by expanded polyglutamine tracts in huntingtin (htt).
- Mutated htt (HD-htt) affects various tissues, but HD symptoms stem from selective neuronal loss.
- The impact of HD-htt on peripheral cell mitochondria remains understudied.
Purpose of the Study:
- To investigate the effects of HD-htt on mitochondrial function in human peripheral blood cells.
- To compare mitochondrial parameters between cells from HD patients and healthy controls.
- To elucidate the mechanism by which HD-htt influences mitochondrial calcium handling and permeability transition.
Main Methods:
- Isolation and functional analysis of mitochondria from lymphoblastoid cell lines (LBM) of HD patients and controls.
- Measurement of respiratory parameters and mitochondrial membrane potential.
- Assessment of calcium retention capacity (CRC) and mitochondrial permeability transition (PT) using multiple methods, including cyclosporin A treatment.
Main Results:
- Respiratory parameters and oxidative phosphorylation were similar between HD-LBM and control LBM.
- HD-LBM exhibited slightly lower State 4 membrane potential compared to controls.
- Mitochondrial calcium handling differed, with HD-LBM showing altered permeability transition dynamics and reduced sensitivity to cyclosporin A, suggesting impaired proton conductance.
Conclusions:
- HD-htt appears to alter mitochondrial function in peripheral cells by promoting low proton conductance.
- This effect is likely mediated through interactions at contact sites, without directly inducing permeability transition or impairing oxidative phosphorylation.
- These findings suggest a broader cellular impact of HD-htt beyond neuronal tissues, potentially contributing to disease pathogenesis.
Abstract:
Huntington's disease (HD) is associated with expansion of polyglutamine tract in a protein named huntingtin (htt) that is expressed in virtually all body tissues. Thus mutated htt (HD-htt) might affect all organs, although clinical manifestations of HD are associated with selective loss of corticostriatal neurons of the brain. In this work we studied how HD-htt affects mitochondria in human peripheral blood cells. We compared various functions of mitochondria isolated from cultured lymphoblastoid cells derived from three HD patients with juvenile onset of the disease (HD-LBM) and three age-matched control (C-LBM) individuals. Respiratory parameters in different metabolic states, with succinate and glutamate plus malate were the same for all control and HD cell lines. State 4 membrane potential in HD-LBM was slightly lower than in C-LBM. The calcium retention capacity (CRC) of mitochondria was estimated using simultaneously several methods to register permeability transition (PT). We found that LBM do not undergo swelling upon Ca2+-induced PT, and do not increase CRC in the presence of ADP + oligomycin. Although each cell line had different CRC values, qualitatively PT was different in C-LBM and HD-LBM. With C-LBM cyclosporin A (CsA) increased CRC significantly, while with HD-LBM CsA was ineffective. In C-LBM depolarization of mitochondria and a large pore opening (PT) always occurred simultaneously. In HD-LBM depolarization occurred at 20-50% lower Ca2+ loads than PT. We suggest that HD-htt promotes low H+ conductance of the mitochondria by interacting with proteins at the contacts sites without directly promoting PT or hampering mitochondrial oxidative phosphorylation.
