ArticleProceedings of the National Academy of Sciences of the United States of America2019
Mutant huntingtin disrupts mitochondrial proteostasis by interacting with TIM23.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers, 1 of them a synthesis that pooled it.
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Who cites it
57 citing papers in PubMed, 1 synthesis or guideline pooled it, 103 citations in OpenAlex.
- Unveiling sex-based differences in Parkinson's disease: a comprehensive meta-analysis of transcriptomic studies.Biology of sex differences · 2022Pooled it
- Metabolic reprogramming is critical to microglial activation in Huntington's disease.JCI insight · 2026Article
- Huntingtin and its allies at the cortico-striatal synapse.Cell death & disease · 2026Review
- Role of mitochondria in neuronal function and survival in the enteric and central nervous systems.Cellular and molecular life sciences : CMLS · 2026Review
- Stress granules as a central hub linking organelle stress, aging, and neurodegeneration.BMB reports · 2026Review
- Oxidative Stress and Lysosomal Dysfunction in Neurodegenerative Diseases: Underlying Mechanisms and Nanotherapeutic Targeting Strategies.Antioxidants (Basel, Switzerland) · 2026Review
- Targeting mitochondria for the treatment of neurodegenerative diseases.Frontiers in neuroscience · 2026Review
- Neuronal mitochondrial disaggregase CLPB ameliorates Huntington's disease pathology in mice.Theranostics · 2026Article
- Article
- Sensing within: Mitochondrial inside-out signal transduction.Cell chemical biology · 2025Review
- AI-Enhanced Transcriptomic Discovery of Druggable Targets and Repurposed Therapies for Huntington's Disease.Brain sciences · 2025Review
- NEDD4L induces mitochondrial dysfunction and neurodegeneration by promoting LIPT2 degradation in Huntington's disease.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62.Nature communications · 2025Article
- Oxidative Stress: Pathological Driver in Chronic Neurodegenerative Diseases.Antioxidants (Basel, Switzerland) · 2025Review
- G9a an Epigenetic Therapeutic Strategy for Neurodegenerative Conditions: From Target Discovery to Clinical Trials.Medicinal research reviews · 2025Review
- Antioxidant and Anti-Inflammatory Defenses in Huntington's Disease: Roles of NRF2 and PGC-1α, and Therapeutic Strategies.Life (Basel, Switzerland) · 2025Review
- Melatonin Deficits Result in Pathologic Metabolic Reprogramming in Differentiated Neurons.Journal of pineal research · 2025Article
- Regulation of Mutant Huntingtin Mitochondrial Toxicity by Phosphomimetic Mutations within Its N-Terminal Region.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Mitochondrial protein import stress.Nature cell biology · 2025Review
- Therapeutic approaches targeting aging and cellular senescence in Huntington's disease.CNS neuroscience & therapeutics · 2024Review
Corrections and comments
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Authors and funding
18 authors at 4 institutions in 1 country.
Funding
Abstract
Mutant huntingtin (mHTT), the causative protein in Huntington's disease (HD), associates with the translocase of mitochondrial inner membrane 23 (TIM23) complex, resulting in inhibition of synaptic mitochondrial protein import first detected in presymptomatic HD mice. The early timing of this event suggests that it is a relevant and direct pathophysiologic consequence of mHTT expression. We show that, of the 4 TIM23 complex proteins, mHTT specifically binds to the TIM23 subunit and that full-length wild-type huntingtin (wtHTT) and mHTT reside in the mitochondrial intermembrane space. We investigated differences in mitochondrial proteome between wtHTT and mHTT cells and found numerous proteomic disparities between mHTT and wtHTT mitochondria. We validated these data by quantitative immunoblotting in striatal cell lines and human HD brain tissue. The level of soluble matrix mitochondrial proteins imported through the TIM23 complex is lower in mHTT-expressing cell lines and brain tissues of HD patients compared with controls. In mHTT-expressing cell lines, membrane-bound TIM23-imported proteins have lower intramitochondrial levels, whereas inner membrane multispan proteins that are imported via the TIM22 pathway and proteins integrated into the outer membrane generally remain unchanged. In summary, we show that, in mitochondria, huntingtin is located in the intermembrane space, that mHTT binds with high-affinity to TIM23, and that mitochondria from mHTT-expressing cells and brain tissues of HD patients have reduced levels of nuclearly encoded proteins imported through TIM23. These data demonstrate the mechanism and biological significance of mHTT-mediated inhibition of mitochondrial protein import, a mechanism likely broadly relevant to other neurodegenerative diseases.
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