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Cited by 43Alzheimer's disease research and treatmentsMitochondrial Function and PathologyDementia and Cognitive Impairment Research

Mitochondria-Targeted Therapeutics for Alzheimer's Disease: The Good, the Bad, the Potential

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Mi, Yashi, Qi, Guoyuan, Brinton, Roberta Diaz, Yin, Fei·2021·Antioxidants & Redox Signaling
DOI 10.1089/ars.2020.8070PMC PMC7891225
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Abstract

Significance: Alzheimer's disease (AD) is the leading cause of dementia. Thus far, 99.6% of clinical trials, including those targeting energy metabolism, have failed to exert disease-modifying efficacy. Altered mitochondrial function and disruption to the brain bioenergetic system have long-been documented as early events during the pathological progression of AD. Recent Advances: While therapeutic approaches that directly promote mitochondrial bioenergetic machinery or eliminate reactive oxygen species have exhibited limited translatability, emerging strategies targeting nonenergetic aspects of mitochondria provide novel therapeutic targets with the potential to modify AD risk and progression. Growing evidence also reveals a critical link between mitochondrial phenotype and neuroinflammation via metabolic reprogramming of glial cells. Critical Issues: Herein, we summarize major classes of mitochondrion-centered AD therapeutic strategies. In addition, the discrepancy in their efficacy when translated from preclinical models to clinical trials is addressed. Key factors that differentiate the responsiveness to bioenergetic interventions, including sex, apolipoprotein E genotype, and cellular diversity in the brain, are discussed. Future Directions: We propose that the future development of mitochondria-targeted AD therapeutics should consider the interactions between bioenergetics and other disease mechanisms, which may require cell-type-specific targeting to distinguish neurons and non-neuronal cells. Moreover, a successful strategy will likely include stratification by metabolic phenotype, which varies by sex and genetic risk profile and dynamically changes throughout the course of disease. As the network of mitochondrial integration expands across intracellular and systems level biology, assessment of intended, the good, versus unintended consequences, the bad, will be required to reach the potential of mitochondrial therapeutics.

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  • These mitochondrial impairments are accompanied by increased ROS generation, mitochondrial DNA damage, and activation of mPTP.

    “These impairments are accompanied by increased ROS generation, mitochondrial DNA damage, and activation of the mitochondrial permeability transition pore (mPTP) [58].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [58]

    The Introduction (page unavailable) links mitochondrial dysfunction in Alzheimer’s disease with increased ROS production and reports mtDNA mutations and injuries. However, the passages found for “mPTP” and “permeability transition pore” do not address activation of that pore, so the source does not support that part of the sentence. (LLM, conf=0.85)

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Authors
Mi, Y., Qi, G., Brinton, R. D., & Yin, F.
Affiliations
  • University of Arizona (US)
  • Center for Innovation in Brain Science, University of Arizona Health Sciences, Tucson, Arizona, USA.
Corresponding author
Yin, Fei
ORCID
Venue
Antioxidants & Redox Signaling
Publisher
SAGE Publications
Published
2021-03-10
Volume
34
Issue
8
Pages
611-630
ISSN
  • 1523-0864 (ISSN-L)
  • 1557-7716
DOI
10.1089/ars.2020.8070
PMC
PMC7891225
OpenAlex
W3010397299
Cited by
43
References
29
Citations by year
2026: 13 · 2025: 8 · 2024: 6 · 2023: 7 · 2022: 5 · 2021: 4
FWCI
0.51
Type
journal article
Language
en
Open access
Licence
www.liebertpub.com/nv/resources-tools/text-and-data-mining-policy/121/ (tdm)
Locations
  • Antioxidants and Redox Signaling (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UA Campus Repository (The University of Arizona) (acceptedVersion)
Funders
National Institute on Aging (R01AG057931, R37AG053589, P01AG026572)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, mitochondrial bioenergetics, reactive oxygen species, neuroinflammation, sex differences, APOE genotype, metabolic phenotyping, cell type-specific targeting, translational failure, clinical trial efficacy
MeSH terms
Alzheimer Disease, Animals, Humans, Mitochondria, Neuroprotective Agents

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