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Mitochondrial Protein Import Dysfunction in Pathogenesis of Neurodegenerative Diseases

Molecular Neurobiology volume 58, pages 1418–1437 (2021)Cite this article

Abstract

Mitochondria play an essential role in maintaining energy homeostasis and cellular survival. In the brain, higher ATP production is required by mature neurons for communication. Most of the mitochondrial proteins transcribe in the nucleus and import in mitochondria through different pathways of the mitochondrial protein import machinery. This machinery plays a crucial role in determining mitochondrial morphology and functions through mitochondrial biogenesis. Failure of this machinery and any alterations during mitochondrial biogenesis underlies neurodegeneration resulting in Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD) etc. Current knowledge has revealed the different pathways of mitochondrial protein import machinery such as translocase of the outer mitochondrial membrane complex, the presequence pathway, carrier pathway, β-barrel pathway, and mitochondrial import and assembly machinery etc. In this review, we have discussed the recent studies regarding protein import machinery, beyond the well-known effects of increased oxidative stress and bioenergetics dysfunctions. We have elucidated in detail how these types of machinery help to import and locate the precursor proteins to their specific location inside the mitochondria and play a major role in mitochondrial biogenesis. We further discuss their involvement in mitochondrial dysfunctioning and the induction of toxic aggregates in neurodegenerative diseases like AD and PD. The review supports the importance of import machinery in neuronal functions and its association with toxic aggregated proteins in mitochondrial impairment, suggesting a critical role in fostering and maintaining neurodegeneration and therapeutic response.

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Acknowledgments

The authors are thankful to the Director. CSIR-IITR manuscript communication number-3658.

Funding

This work was supported by the Lady Tata Memorial-UK Young Scientist Grant, Science and Engineering Research Board (SERB), New Delhi, EMR Grant (EMR/2016/001933), Department of Biotechnology, New Delhi Research Grant (BT/PR15819/MED/31/322/2015), Department of Biotechnology, National Bioscience Award Research grant (BT/HRD/NBA/38/07/2018), and CSIR Network Projects (BSC-0115 and BSC-0111) to RKC.

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  1. Developmental Toxicology Laboratory, Systems Toxicology and Health Risk Assessment Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Vishvigyan Bhavan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh, 226001, India

    Shweta Goyal & Rajnish Kumar Chaturvedi

  2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

    Shweta Goyal & Rajnish Kumar Chaturvedi

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  1. Shweta Goyal
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Correspondence to Rajnish Kumar Chaturvedi.

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Goyal, S., Chaturvedi, R.K. Mitochondrial Protein Import Dysfunction in Pathogenesis of Neurodegenerative Diseases. Mol Neurobiol 58, 1418–1437 (2021). https://doi.org/10.1007/s12035-020-02200-0

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Keywords

  • Mitochondria
  • Mitochondrial biogenesis
  • Protein import machinery
  • Neurodegeneration
  • Alzheimer’s disease
  • Parkinson’s disease