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Updated: Dec 11, 2025
11:22
Generation of Native, Untagged Huntingtin Exon1 Monomer and Fibrils Using a SUMO Fusion Strategy
Published on: June 27, 2018
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Mutant huntingtin does not cross the mitochondrial outer membrane.
James Hamilton1, Tatiana Brustovetsky1, Rajesh Khanna2
1Department of Pharmacology and Toxicology.
Human Molecular Genetics
|August 22, 2020
Summary
Mutant huntingtin (mHTT) is found on the outer mitochondrial membrane, not inside. This finding refutes the idea that mHTT inhibits mitochondrial protein import.
Area of Science:
- Mitochondrial biology
- Neurodegenerative diseases
- Cellular biochemistry
Background:
- Mutant huntingtin (mHTT) is linked to mitochondria, but its precise location is debated.
- A recent hypothesis suggested mHTT in the intermembrane space inhibits protein import via TIM23.
Purpose of the Study:
- To definitively determine the mitochondrial localization of mutant huntingtin (mHTT).
- To investigate if mHTT inhibits mitochondrial protein import by interacting with TIM23.
Main Methods:
- Mitochondria isolated from YAC128 mouse brains and postmortem human brain tissues.
- Mitochondria subjected to alkali treatment and limited trypsin digestion.
- Mitochondrial purification using Percoll gradients and anti-TOM22 microbeads.
Main Results:
- Mutant huntingtin (mHTT) is located on the cytosolic side of the mitochondrial outer membrane (MOM) and does not cross it.
- Expression of key mitochondrial proteins and respiratory function were similar in mutant and wild-type mitochondria.
- No deficit in mitochondrial protein import was observed.
Conclusions:
- Mutant huntingtin (mHTT) does not enter the mitochondrial intermembrane space.
- The hypothesis that mHTT inhibits mitochondrial protein import by interacting with TIM23 is refuted.
- Mitochondrial function and protein import are not impaired by mHTT's location on the outer mitochondrial membrane.
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