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Cited by 16Mitochondrial Function and PathologyAutophagy in Disease and TherapyParkinson's Disease Mechanisms and Treatments

Synaptic mitochondria in aging and neurodegenerative diseases: Functional decline and vulnerability

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Cicali, Karina A., Torres, Angie K., Tapia-Rojas, Cheril·2026·Neural Regeneration Research
DOI 10.4103/nrr.nrr-d-24-01571PMC PMC13211840
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Abstract

Aging is a physiological and complex process produced by accumulative age-dependent cellular damage, which significantly impacts brain regions like the hippocampus, an essential region involved in memory and learning. A crucial factor contributing to this decline is the dysfunction of mitochondria, particularly those located at synapses. Synaptic mitochondria are specialized organelles that produce the energy required for synaptic transmission but are also important for calcium homeostasis at these sites. In contrast, non-synaptic mitochondria primarily involve cellular metabolism and long-term energy supply. Both pools of mitochondria differ in their form, proteome, functionality, and cellular role. The proper functioning of synaptic mitochondria depends on processes such as mitochondrial dynamics, transport, and quality control. However, synaptic mitochondria are particularly vulnerable to age-associated damage, characterized by oxidative stress, impaired energy production, and calcium dysregulation. These changes compromise synaptic transmission, reducing synaptic activity and cognitive decline during aging. In the context of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s, the decline of synaptic mitochondrial function is even more pronounced. These diseases are marked by pathological protein accumulation, disrupted mitochondrial dynamics, and heightened oxidative stress, accelerating synaptic dysfunction and neuronal loss. Due to their specialized role and location, synaptic mitochondria are among the first organelles to exhibit dysfunction, underscoring their critical role in disease progression. This review delves into the main differences at structural and functional levels between synaptic and non-synaptic mitochondria, emphasizing the vulnerability of synaptic mitochondria to the aging process and neurodegeneration. These approaches highlight the potential of targeting synaptic mitochondria to mitigate age-associated cognitive impairment and synaptic degeneration. This review emphasizes the distinct vulnerabilities of hippocampal synaptic mitochondria, highlighting their essential role in sustaining brain function throughout life and their promise as therapeutic targets for safeguarding the cognitive capacities of people of advanced age.

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Cited by

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Authors
Cicali, K. A., Torres, A. K., & Tapia-Rojas, C.
Affiliations
  • Universidad San Sebastián (CL)
  • Fundación Ciencia and Vida (CL)
  • Laboratory of Neurobiology of Aging, Centro Científico y Tecnológico de Excelencia Ciencia & Vida, Fundación Ciencia & Vida, Santiago, Chile
ORCID
Venue
Neural Regeneration Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2025-06-19
Volume
21
Issue
6
Pages
2145-2152
ISSN
  • 1673-5374 (ISSN-L)
  • 1876-7958
DOI
10.4103/nrr.nrr-d-24-01571
PMC
PMC13211840
OpenAlex
W4411437713
Cited by
16
References
5
Citations by year
2026: 14 · 2025: 2
FWCI
4.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Neural Regeneration Research (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
synaptic mitochondria, mitochondrial dysfunction, brain aging, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Huntington's disease, hippocampus, synaptic transmission, calcium homeostasis, oxidative stress, mitochondrial dynamics, mitochondrial quality control, cognitive decline, synaptic degeneration, therapeutic target

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