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Sex differences in mitochondrial (dys)function: Implications for neuroprotection
Open accessAbstract
Decades of research have revealed numerous differences in brain structure size, connectivity and metabolism between males and females. Sex differences in neurobehavioral and cognitive function after various forms of central nervous system (CNS) injury are observed in clinical practice and animal research studies. Sources of sex differences include early life exposure to gonadal hormones, chromosome compliment and adult hormonal modulation. It is becoming increasingly apparent that mitochondrial metabolism and cell death signaling are also sexually dimorphic. Mitochondrial metabolic dysfunction is a common feature of CNS injury. Evidence suggests males predominantly utilize proteins while females predominantly use lipids as a fuel source within mitochondria and that these differences may significantly affect cellular survival following injury. These fundamental biochemical differences have a profound impact on energy production and many cellular processes in health and disease. This review will focus on the accumulated evidence revealing sex differences in mitochondrial function and cellular signaling pathways in the context of CNS injury mechanisms and the potential implications for neuroprotective therapy development.
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“important sex differences exist in mitochondrial function [14–16], substrate utilization, and insulin sensitivity [17–24], immune responses [25–28], muscle morphology and body composition [29–32], iron metabolism [33–40], thermoregulation [41–44], hydration [45,46]{Sims, 2008 #55, [47–53], appetite control [54–59], and energy availability and endocrine function [60–65].”
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Casagrande, S., Gómez‐Laich, A., & Dell’Omo, G. (2026) · Biology Letters · doi:10.1098/rsbl.2026.0225
Belczyk, M., Gawędzka, A., Drąg, J., Stelmach, O., & Knapik-Czajka, M. E. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27156791
Update on sex-specific microglia contribution to early synaptic dysfunction in Alzheimer’s disease
Roux, C. M., & Krantic, S. M. (2026) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2026.1905780
Mathias, K., Tiscoski, A. D. B., de Rezende, V. L., BARBOSA, C. D. G. M., Piacentini, N., Dal‐Pizzol, F., Barichello, T., & Petronilho, F. C. (2026) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2026.101286
Pislaru, A., Roudier, É., Rezvan, O., Breadmore, C., Fathi, M., Nader, G., AlZaim, I., Nwadozi, E., Lee, G., Yavari, E., et al. (2026) · Angiogenesis · doi:10.1007/s10456-026-10093-1
Yousuf, S., Atif, F., & Stein, D. G. (2026) · Journal of Alzheimer s Disease Reports · doi:10.1177/25424823261498338
Metadata
- Authors
- Demarest, T. G., & McCarthy, M. M.
- Affiliations
- University of Maryland, Baltimore (US)
- Corresponding author
- Demarest, Tyler G.
- Venue
- Journal of Bioenergetics and Biomembranes
- Published
- 2014-10-08
- Volume
- 47
- Issue
- 1-2
- Pages
- 173-188
- ISSN
- 0145-479X (ISSN-L)
- 1573-6881
- PMC
- PMC4988325
- OpenAlex
- W1980632245
- Cited by
- 192
- References
- 169
- Citations by year
- 2026: 14 · 2025: 23 · 2024: 24 · 2023: 23 · 2022: 17 · 2021: 28 · 2020: 18 · 2019: 16 · 2018: 13 · 2017: 11 · 2016: 4 · 2015: 1
- FWCI
- 0.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Bioenergetics and Biomembranes (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD016596)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Neurology › Neuroprotection in Cerebral Ischemia
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
- Keywords
- sex differences, mitochondrial dysfunction, neuroprotection, central nervous system injury, brain energy metabolism, cell death signaling, gonadal hormones, sex hormones, neuroprotective therapy
- MeSH terms
- Adult, Central Nervous System, Central Nervous System Diseases, Energy Metabolism, Female, Humans, Male, Mitochondria, Sex Characteristics, Mitochondrial Diseases
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