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Full text release has been delayed at the author's request until January 20, 2025

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Regulation of MICOS Complex in Neurodegenerative Diseases

Shang, Yutong
http://rave.ohiolink.edu/etdc/view?acc_num=case1670434756957449

Abstract Details

, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
Neurodegenerative diseases are nervous system disorders characterized by selective types of neuronal cell death. The causal factors for the different diseases vary, and clear molecular and cellular pathways underlying the pathogeneses remain elusive. However, accumulating evidence has suggested that mitochondrial dysfunction plays a critical role in disease-associated cell death due to the enormous energy demands of neurons. To improve the efficiency of oxidative respiration and generate more ATP, proteins on mitochondrial inner membrane form a complex adjacent to cristae junction. This complex, called the mitochondrial contact site and cristae organizing system (MICOS), maintains proper cristae morphology and stabilizes the intracristal environment for important mitochondrial functions, such as oxidative respiration. Previous studies have revealed that disruption of the MICOS leads to similar mitochondrial defects as in neurodegenerative diseases. This suggests MICOS loss as an upstream event of mitochondrial dysfunction and neuronal cell death in these disorders. In the present study, MICOS disruption was found in both Alzheimer’s disease (AD) and Huntington’s disease (HD) with different target components and molecular mechanisms. CHCHD6 was specifically connected to AD through a feedback loop that lowered CHCHD6 levels and increased APP processing. In cellular and animal AD models and human AD brains, the APP intracellular domain fragment inhibited CHCHD6 transcription by binding its promoter. CHCHD6 and APP bound to and stabilized each other. Reduced CHCHD6 enhanced APP accumulation on mitochondria-associated ER membranes and accelerated APP processing and induced mitochondrial dysfunction and neuronal cholesterol accumulation, promoting the amyloid pathology. Compensation for CHCHD6 loss in an AD mouse model ameliorated the AD-associated neuropathology and cognitive impairment. In contrast to AD, the specific MICOS component contributing to MICOS loss in HD was mitofilin. Consistent loss of mitofilin was found in HD cells, mice, and patients. Overexpression of mitofilin rescued mitochondrial dysfunction in HD cells and reduced neuropathology and motor deficits in HD mice. Even though different disease-causing factors impair different components of the MICOS, the assembly of the complex was consistently lost. Thus, our findings reveal that targeting the MICOS complex may be a potential translational strategy in neurodegenerative diseases. .
George Dubyak (Committee Chair)
Corey Smith (Committee Member)
Xin Qi (Advisor)
Wencheng Xiong (Committee Member)
Sudha Chakrapani (Committee Member)
149 p.
Biology; Biomedical Research; Cellular Biology; Molecular Biology; Neurosciences; Pathology; Physiology
Alzheimer’s disease; Huntington's disease; mitochondria; MICOS complex; neuroprotection; neurodegeneration

Recommended Citations

Citations

  • Shang, Y. (2022). Regulation of MICOS Complex in Neurodegenerative Diseases [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1670434756957449

    APA Style (7th edition)

  • Shang, Yutong. Regulation of MICOS Complex in Neurodegenerative Diseases. 2022. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1670434756957449.

    MLA Style (8th edition)

  • Shang, Yutong. "Regulation of MICOS Complex in Neurodegenerative Diseases." Doctoral dissertation, Case Western Reserve University, 2022. http://rave.ohiolink.edu/etdc/view?acc_num=case1670434756957449

    Chicago Manual of Style (17th edition)

case1670434756957449
© 2022, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.