Mutant huntingtin disrupts mitochondrial proteostasis by interacting with TIM23.
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.
['Yablonska|Svitlana|S|', 'Ganesan|Vinitha|V|', 'Ferrando|Lisa M|LM|', 'Kim|JinHo|J|', 'Pyzel|Anna|A|', 'Baranova|Oxana V|OV|', 'Khattar|Nicolas K|NK|', 'Larkin|Timothy M|TM|', 'Baranov|Sergei V|SV|', 'Chen|Ning|N|', 'Strohlein|Colleen E|CE|', 'Stevens|Donté A|DA|', 'Wang|Xiaomin|X|', 'Chang|Yue-Fang|YF|', 'Schurdak|Mark E|ME|', 'Carlisle|Diane L|DL|', 'Minden|Jonathan S|JS|', 'Friedlander|Robert M|RM|']
D002460:Cell Line D002467:Cell Nucleus D002540:Cerebral Cortex D003342:Corpus Striatum D006801:Humans D000071058:Huntingtin Protein D006816:Huntington Disease D008928:Mitochondria D033681:Mitochondrial Membrane Transport Proteins D051336:Mitochondrial Membranes D000090622:Mitochondrial Precursor Protein Import Complex Proteins D024101:Mitochondrial Proteins D050505:Mutant Proteins D011485:Protein Binding D020543:Proteome D000074702:Proteostasis
mutant huntingtin proteostasis TIM23 mitochondria Huntington’s disease