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The Role of Mitochondria in Neurodegenerative Diseases: the Lesson from Alzheimer’s Disease and Parkinson’s Disease

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Abstract

Although the pathogenesis of neurodegenerative diseases is still widely unclear, various mechanisms have been proposed and several pieces of evidence are supportive for an important role of mitochondrial dysfunction. The present review provides a comprehensive and up-to-date overview about the role of mitochondria in the two most common neurodegenerative disorders: Alzheimer’s disease (AD) and Parkinson’s disease (PD). Mitochondrial involvement in AD is supported by clinical features like reduced glucose and oxygen brain metabolism and by numerous microscopic and molecular findings, including altered mitochondrial morphology, impaired respiratory chain function, and altered mitochondrial DNA. Furthermore, amyloid pathology and mitochondrial dysfunction seem to be bi-directionally correlated. Mitochondria have an even more remarkable role in PD. Several hints show that respiratory chain activity, in particular complex I, is impaired in the disease. Mitochondrial DNA alterations, involving deletions, point mutations, depletion, and altered maintenance, have been described. Mutations in genes directly implicated in mitochondrial functioning (like Parkin and PINK1) are responsible for rare genetic forms of the disease. A close connection between alpha-synuclein accumulation and mitochondrial dysfunction has been observed. Finally, mitochondria are involved also in atypical parkinsonisms, in particular multiple system atrophy. The available knowledge is still not sufficient to clearly state whether mitochondrial dysfunction plays a primary role in the very initial stages of these diseases or is secondary to other phenomena. However, the presented data strongly support the hypothesis that whatever the initial cause of neurodegeneration is, mitochondrial impairment has a critical role in maintaining and fostering the neurodegenerative process.

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Abbreviations

AD:

Alzheimer’s disease

PD:

Parkinson’s disease

APP:

amyloid precursor protein

PET:

positron emission tomography

mtDNA:

mitochondrial DNA

CR:

control region

ABAD:

Aβ-binding alcohol dehydrogenase

UPRmt :

mitochondrial unfolded protein response

SN:

substantia nigra

α-syn:

alpha-synuclein

MPTP:

1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine

PEO:

progressive external ophthalmoplegia

TOM20:

translocase of the outer membrane 20

MAM:

mitochondria-associated endoplasmic reticulum membranes

MSA:

multiple system atrophy

CoQ10:

coenzyme Q10

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Acknowledgments

The support from Associazione Amici del Centro Dino Ferrari is gratefully acknowledged.

Funding

The financial support was received from the Fresco Institute for Parkinson’s and Movement Disorders.

Author information

Authors and Affiliations

  1. IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

    Giacomo Monzio Compagnoni, Alessio Di Fonzo, Stefania Corti, Giacomo P. Comi & Nereo Bresolin

  2. Department of Neurology, School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy

    Giacomo Monzio Compagnoni

  3. Department of Neurology, Khurana Laboratory, Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Giacomo Monzio Compagnoni

  4. Department of Pathophysiology and Transplantation, Neuroscience Section, Dino Ferrari Center, University of Milan, Milan, Italy

    Stefania Corti, Giacomo P. Comi & Nereo Bresolin

  5. Division of Neuroscience and Laboratory of Neurogenetics, National Institute on Aging, National Institute of Health, Bethesda, MD, USA

    Eliezer Masliah

Authors
  1. Giacomo Monzio Compagnoni
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  2. Alessio Di Fonzo
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  3. Stefania Corti
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  4. Giacomo P. Comi
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  5. Nereo Bresolin
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  6. Eliezer Masliah
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Contributions

Conceptualization and design: GMC; acquisition and analysis of data: GMC; initial writing of the manuscript: GMC; critical revision of the manuscript for important intellectual content: GMC, ADF, SC, GPC, NB, EM.

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Correspondence to Giacomo Monzio Compagnoni.

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Monzio Compagnoni, G., Di Fonzo, A., Corti, S. et al. The Role of Mitochondria in Neurodegenerative Diseases: the Lesson from Alzheimer’s Disease and Parkinson’s Disease. Mol Neurobiol 57, 2959–2980 (2020). https://doi.org/10.1007/s12035-020-01926-1

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  • DOI: https://doi.org/10.1007/s12035-020-01926-1

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