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Cited by 11Mitochondrial Function and PathologyAutophagy in Disease and TherapyMetabolism and Genetic Disorders

Preclinical models of mitochondrial dysfunction: mtDNA and nuclear-encoded regulators in diverse pathologies

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Miller, Dalia M., Archer, Stephen L., Dunham-Snary, Kimberly J.·2025·Frontiers in Aging
DOI 10.3389/fragi.2025.1585508PMC PMC12230096
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Abstract

Mitochondrial-driven diseases encompass a diverse group of single-gene and complex disorders, all linked to mitochondrial dysfunction, with significant impacts on human health. While there are rare mitochondrial diseases in which the primary defect resides in mutations in mitochondrial DNA, it is increasingly clear that acquired mitochondrial dysfunction, both genetically- and epigenetically-mediated, complicates common complex diseases, including diabetes, cardiovascular disease and ischemia reperfusion injury, cancer, pulmonary hypertension, and neurodegenerative diseases. It is also recognized that mitochondrial abnormalities not only act by altering metabolism but, through effects on mitochondrial dynamics, can regulate numerous cellular processes including intracellular calcium handling, cell proliferation, apoptosis and quality control. This review examines the crucial role of preclinical models in advancing our understanding of mitochondrial genetic contributions to these conditions. It follows the evolution of models of mitochondrial-driven diseases, from earlier in vitro and in vivo systems to the use of more innovative approaches, such as CRISPR-based gene editing and mitochondrial replacement therapies. By assessing both the strengths and limitations of these models, we highlight their contributions to uncovering disease mechanisms, identifying therapeutic targets, and facilitating novel discoveries. Challenges in translating preclinical findings into clinical applications are also addressed, along with strategies to enhance the accuracy and relevance of these models. This review outlines the current state of the field, the future trajectory of mitochondrial disease modeling, and its potential impact on patient care.

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  • Cybrid models demonstrate that mitochondrial defects alone can recapitulate key AD phenotypes, including decreased complex IV activity, increased ROS generation, synaptic dysfunction, and enhanced Aβ and phosphorylated tau accumulation.

    “Evidence from cytoplasmic hybrid (cybrid) models, where mitochondria from AD patients are transferred into mtDNA-depleted cells, demonstrates that mitochondrial defects alone can recapitulate key AD phenotypes, including decreased complex IV activity, increased ROS generation, synaptic dysfunction, and enhanced Aβ and phosphorylated tau accumulation [59, 60].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [60]

    Section 1.3.1 describes cybrids as mtDNA-depleted cells receiving donor mitochondria and says they can isolate the influence of introduced mtDNA. Sections 1.3 and 1.4 report respiratory-chain defects and oxidative stress in cybrid models of other diseases, but our copy does not report AD-patient cybrids or the claimed synaptic dysfunction, Aβ accumulation, and phosphorylated tau accumulation. The complex IV reduction it describes is in MELAS cybrids, not AD cybrids. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Miller, D. M., Archer, S. L., & Dunham-Snary, K. J.
Affiliations
Queen's University (CA)
ORCID
Archer, Stephen L.
Venue
Frontiers in Aging
Publisher
Frontiers Media SA
Published
2025-06-23
Volume
6
Pages
1585508-1585508
ISSN
2673-6217 (ISSN-L)
DOI
10.3389/fragi.2025.1585508
PMC
PMC12230096
OpenAlex
W4411572680
Cited by
11
References
6
Citations by year
2026: 7 · 2025: 4
FWCI
0.90
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Aging (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Canadian Institutes of Health Research
  • Canada Research Chairs
  • Canada Foundation for Innovation
  • Faculty of Health Sciences, Queen’s University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
mitochondrial dysfunction, mitochondrial disease, mitochondrial DNA mutations, preclinical disease models, mitochondrial replacement therapy, CRISPR gene editing, mitochondrial dynamics, complex diseases, diabetes mellitus, cardiovascular disease, ischemia-reperfusion injury, cancer, pulmonary hypertension, neurodegenerative diseases, epigenetic regulation, mitochondrial quality control, clinical translation

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