Mitochondria: The Overlooked Link in Gut-Brain Communication

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The gut-brain connection is well-established, but there’s more to this dynamic relationship than meets the eye. A vital yet often overlooked component of this axis is the mitochondria—organelles that extend their influence far beyond metabolism.  If you read our January blog post on breaking the cycle of mitochondrial dysfunction, you’ve seen how impaired mitochondria contribute to a range of health concerns. When it comes to mental health, the case is no different, though the mechanisms involved are unique.  Beyond generating ATP, mitochondria influence inflammatory responses, gut microbiota balance, and stress resilience. Emerging research reveals an intricate interplay between mitochondrial function, the gut, and mental health. Understanding this relationship could hold the missing link in optimizing psychological wellness. 

The Gut-Brain-Mitochondria Axis 

A decline in mitochondrial function drives oxidative stress and inflammation, compromising the microbiome, gut barrier integrity, sleep, and neurotransmitter production, which in turn contributes to anxiety and mood imbalances.1,3  Accumulating evidence suggests a bidirectional relationship—mitochondrial dysfunction fuels anxiety, while chronic stress and anxiety impair mitochondrial function.2 Mechanisms include:1,3,4 
  • Gut permeability & dysbiosis: Compromised mitochondria weaken intestinal barrier function, increasing susceptibility to “leaky gut” and microbial imbalances. 
  • Neurotransmitter production & stress regulation: Mitochondria are involved in serotonin and dopamine synthesis, both essential for mood and stress responses. 
  • Oxidative stress & inflammation: Excessive reactive oxygen species (ROS) production from dysfunctional mitochondria can trigger systemic inflammation, further impacting gut health and brain function. 
 Studies indicate that the nucleus accumbens, a brain region involved in motivation and reward processing, may be especially susceptible to mitochondrial dysfunction. Animal studies demonstrate that impaired mitochondrial function in this area lowers social rank in competitive settings, mimicking the social withdrawal often seen in anxiety-prone individuals. Conversely, interventions that support mitochondrial health, such as nicotinamide (vitamin B3), have been shown to mitigate these effects.2,5  At the cellular level, mitochondria act as both mediators and targets of the stress response. When stress stimulates the adrenal glands, their mitochondria produce cortisol, which in turn influences mitochondrial function across the body, including in the brain. While this adaptation is beneficial short-term, chronic stress disrupts mitochondrial function, leading to energy deficits, neuroinflammation, and increased ROS production—factors that contribute to fatigue, cognitive impairment, and emotional instability.4   

The Gut’s Influence on Mitochondria and Mental Health 

Just as mitochondria influence gut health, the gut microbiota can impact mitochondrial function and stress resilience in several ways:2,3,6,7 
  • Short-chain fatty acids (SCFAs): Beneficial gut bacteria produce SCFAs like butyrate, which help regulate mitochondrial energy metabolism and reduce oxidative stress. 
  • Inflammatory cytokines: Dysbiosis-driven inflammation damages mitochondria, exacerbating fatigue, brain fog, and anxiety. 
  • Microbiota-derived neurotransmitters: Gut bacteria produce compounds like GABA and serotonin, directly influencing mitochondrial function and stress adaptation. 
Recent studies suggest that psychobiotics, such as Lactobacillus helveticus R0052, and postbiotics, including pasteurized Akkermansia muciniphila, may exert anxiolytic effects by enhancing mitochondrial function, altering neurotransmitter activity, and mitigating neuroinflammation.2,6,7   

Optimizing the Gut-Brain-Mitochondria Axis 

The implications for therapeutic interventions are profound. Strategies aimed at restoring mitochondrial health, managing perceived stress, optimizing circadian rhythm, and targeting gut health may offer comprehensive avenues for alleviating anxiety and stress-related disorders.3,4,6   Beyond gut-supportive psychobiotics and postbiotics, there are several well-researched considerations for maintaining healthy physiological function in these interconnected systems. For instance: 
  • Nutrients: Vitamin B6, folate, and magnesium each contribute to sustaining a healthy mood, sleep cycles, and mitochondrial function.8-15 
  • Herbs: Ashwagandha (Withania somnifera), also known as Indian ginseng, is one of the most highly regarded herbs today. Renowned for its benefits in mitochondrial health, oxidative stress reduction, sleep support, and both cardioprotective and neuroprotective properties, it has earned its strong reputation.16 Another well-studied botanical, lemon balm (Melissa officinalis), has been shown to influence neurotransmitter pathways, including GABA and serotonin, supporting relaxation and emotional balance.17 
As research continues to unfold, the gut-brain-mitochondria axis presents an exciting frontier for understanding and addressing neuropsychiatric disorders. By targeting mitochondrial health, we may unlock novel approaches for fostering a healthier gut and emotional resilience.   

References 

  1. Filiou MD, Sandi C. Anxiety and Brain Mitochondria: A Bidirectional Crosstalk. Trends in Neurosciences. 2019;42(9):573-588. doi:https://doi.org/10.1016/j.tins.2019.07.002
  2. Qiao L, Yang G, Wang P, Xu C. The Potential Role of Mitochondria in the Microbiota-Gut-Brain Axis: Implications for Brain Health. Pharmacological Research. 2024;209:107434-107434. doi:https://doi.org/10.1016/j.phrs.2024.107434
  3. Wang Q, Lu M, Zhu X, et al. Brain Mitochondrial Dysfunction: A Possible Mechanism Links Early Life Anxiety to Alzheimer’s Disease in Later Life. Aging and disease. 2022;13(4):1127. doi:https://doi.org/10.14336/ad.2022.0221
  4. Daniels TE, Olsen EM, Tyrka AR. Stress and Psychiatric Disorders: The Role of Mitochondria. Annual Review of Clinical Psychology. 2020;16(1):165-186. doi:https://doi.org/10.1146/annurev-clinpsy-082719-104030
  5. Hollis F, van der Kooij MA, Zanoletti O, Lozano L, Cantó C, Sandi C. Mitochondrial function in the brain links anxiety with social subordination. Proceedings of the National Academy of Sciences. 2015;112(50):15486-15491. doi:https://doi.org/10.1073/pnas.1512653112
  6. Misera A, Marlicz W, Podkówka A, Łoniewski I, Skonieczna-Żydecka K. Possible application of Akkermansia muciniphila in stress management. Microbiome Research Reports. 2024;3(4). doi:https://doi.org/10.20517/mrr.2023.81
  7. Wallace CJK, Milev RV. The Efficacy, Safety, and Tolerability of Probiotics on Depression: Clinical Results From an Open-Label Pilot Study. Frontiers in Psychiatry. 2021;12. doi:https://doi.org/10.3389/fpsyt.2021.618279
  8. Kronenberg G, Colla M, Endres M. Folic Acid, Neurodegenerative and Neuropsychiatric Disease. Curr Mol Med. 2009;9(3):315-323. doi:https://doi.org/10.2174/156652409787847146
  9. Field DT, Cracknell RO, Eastwood JR, et al. High‐dose Vitamin B6 supplementation reduces anxiety and strengthens visual surround suppression. Human Psychopharmacology: Clinical and Experimental. 2022;37(6). doi:https://doi.org/10.1002/hup.2852
  10. Ciapaite J, van Roermund CWT, Bosma M, et al. Maintenance of cellular vitamin B6 levels and mitochondrial oxidative function depend on pyridoxal 5’-phosphate homeostasis protein. The Journal of biological chemistry. 2023;299(9):105047. doi:https://doi.org/10.1016/j.jbc.2023.105047
  11. Noah L, Dye L, Bois De Fer B, Mazur A, Pickering G, Pouteau E. Effect of magnesium and vitamin B6 supplementation on mental health and quality of life in stressed healthy adults: Post‐hoc analysis of a randomised controlled trial. Stress and Health. 2021;37(5). doi:https://doi.org/10.1002/smi.3051
  12. Mah J, Pitre T. Oral magnesium supplementation for insomnia in older adults: a Systematic Review & Meta-Analysis. BMC Complementary Medicine and Therapies. 2021;21(1). doi:https://doi.org/10.1186/s12906-021-03297-z
  13. Boyle N, Lawton C, Dye L. The Effects of Magnesium Supplementation on Subjective Anxiety and Stress—A Systematic Review. Nutrients. 2017;9(5):429. doi:https://doi.org/10.3390/nu9050429
  14. Kumar A, Mehan S, Tiwari A, et al. Magnesium (Mg2+): Essential Mineral for Neuronal Health: From Cellular Biochemistry to Cognitive Health and Behavior Regulation. Current Pharmaceutical Design. 2024;30. doi:https://doi.org/10.2174/0113816128321466240816075041
  15. Kannan K, Jain SK. Effect of vitamin B 6 on oxygen radicals, mitochondrial membrane potential, and lipid peroxidation in H 2 O 2 -treated U937 monocytes. Free Radical Biology and Medicine. 2004;36(4):423-428. doi:https://doi.org/10.1016/j.freeradbiomed.2003.09.012
  16. Dar NJ, Hamid A, Ahmad M. Pharmacologic overview of Withania somnifera, the Indian Ginseng. Cellular and molecular life sciences: CMLS. 2015;72(23):4445-4460. doi:https://doi.org/10.1007/s00018-015-2012-1
  17. Mathews IM, Eastwood J, Lamport DJ, Romain Le Cozannet, Pascale Fanca-Berthon, Williams CM. Clinical Efficacy and Tolerability of Lemon Balm (Melissa officinalis L.) in Psychological Well-Being: A Review. Nutrients. 2024;16(20):3545-3545. doi:https://doi.org/10.3390/nu16203545