Could Targeting Mitochondria be the Key to Treating Psychosis?




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One of the hottest cellular organelles of the year so far has to be mitochondria. Deleting them has been shown to reverse cellular aging, mitochondria transplants have been shown to reverse pulmonary hypertension, and they are promising targets for developing cures for and understanding neurodegenerative diseases like Parkinson’s, Alzheimer’s and dementia.

To add to the list, scientists the world over are revealing that mitochondrial dysfunction may be a central component of major psychosis (schizophrenia, and in particular bipolar disorder) and perhaps other mental illnesses. Importantly, this means that re-establishing healthy mitochondrial function may be the key to successful treatments and therapies.

Once free-living bacteria that were engulfed by another cell over a billion years ago, mitochondria are now best known as the energy providing powerhouses of our cells. They are also vital to other cellular processes including the formation of reactive oxygen species, cell cycle/growth and survival, balancing calcium ion levels, and neurotransmission.

Multiple lines of scientific evidence indicate that mitochondrial abnormalities and dysfunction are critically involved in psychosis, but what exactly is going on in a cell to create this dysfunction is not yet fully understood.

There are many complex, intertwined molecular pathways that collectively support the healthy functioning of mitochondria, and that is why multiple different abnormalities and mutant molecules can cause mitochondrial dysfunction that impairs neuronal functioning and can cause death of neurons in schizophrenia and bipolar disorder.

Authors of a recent review published in the Canadian Journal of Psychiatry state that:

Bipolar disorder and schizophrenia are complex diseases that cannot be characterized by a singular narrow pathway. Rather, numerous subtle alterations likely converge upon particular pathways (i.e., mitochondrial function) to produce functional alterations.

Some of the earliest points in these mitochondrial function-linked pathways that something could go wrong with and promote psychosis include:

  1. Mutations and altered expression of nuclear and mitochondrial genes

    Mitochondria have their own DNA called mtDNA that we inherit from our mothers, and our cells have their own double stranded DNA, one strand inherited from our mother, the other our father. There are many heritable mutations in both mtDNA and DNA that have been reported in bipolar disorder and schizophrenia that can alter mitochondrial function. Similarly, gene-environment interactions, where our life experiences and stresses can epigenetically alter how genes are expressed, have been identified for genes that are necessary for healthy mitochondrial function in people with major psychosis.

  2. Altered mitochondrial dynamics and trafficking
    Initial investigations suggest a role for altered mitochondrial dynamics and trafficking in schizophrenia, although these processes have not yet been extensively explored in schizophrenia or bipolar disorder. Impairment in mitochondrial trafficking (i.e. the movement and localization of mitochondria within neurons) can produce alterations in neurotransmitter release and synaptic function. Impairment in mitochondrial dynamics (i.e. how mitochondria divide and multiply as well as fuse together in the formation of large networks of 1000s of mitochondria per cell) has been suggested to lead to altered neural connectivity.
  3. Perturbed calcium ion flux and cell signalling
    Calcium ions are essential to the synchronization of neuronal electric activity, which is mediated by mitochondria. It also acts as an intracellular signal integral to the functioning of neurons, eliciting responses such as altered gene expression, cell death/survival, cell metabolism and neurotransmitter release at neuronal synapses. It’s a cyclic relationship in the brain of those with psychosis, where disruptions in either mitochondrial function or calcium ion flux have the potential to exacerbate one another. Impairments in calcium signalling can lead to mitochondrial dysfunction, while impairments in mitochondrial function can lead to problems with calcium signalling.

The future: Mitochondria as a target for treating psychosis

Much more intensive research is required to better understand the complex processes involved in the dysfunction of mitochondria in mental disorders, and how treatments can restore their function.

Although not confirmed in patients with psychosis, physical exercise may be one of the best non-pharmacological strategies used to reverse brain dysfunction. Endurance training involves adaptations that can lead to the upregulation of tissue-protective mechanisms, including increased mitochondrial biogenesis and function, and improvement in antioxidant networks, leading to more effective control of free radical production.

Ultimately, further research could lead to the prescription of lifestyle changes, interventions, therapies and even mitochondria-protecting drugs. It may be that by helping restore mitochondrial biogenesis and function, this can improve the chances of successfully treating psychosis, and, if preliminary research findings are valid, perhaps mood disorders and other mental illnesses too.

References

Anglin, R. (2016). Mitochondrial Dysfunction in Psychiatric Illness The Canadian Journal of Psychiatry, 61 (8), 444-445 DOI: 10.1177/0706743716646361

Correia?Melo, C., Marques, F., Anderson, R., Hewitt, G., Hewitt, R., Cole, J., Carroll, B., Miwa, S., Birch, J., Merz, A., Rushton, M., Charles, M., Jurk, D., Tait, S., Czapiewski, R., Greaves, L., Nelson, G., Bohlooly?Y, M., Rodriguez?Cuenca, S., Vidal?Puig, A., Mann, D., Saretzki, G., Quarato, G., Green, D., Adams, P., von Zglinicki, T., Korolchuk, V., & Passos, J. (2016). Mitochondria are required for pro?ageing features of the senescent phenotype The EMBO Journal, 35 (7), 724-742 DOI: 10.15252/embj.201592862

Di Maio, R., Barrett, P., Hoffman, E., Barrett, C., Zharikov, A., Borah, A., Hu, X., McCoy, J., Chu, C., Burton, E., Hastings, T., & Greenamyre, J. (2016).  -Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinsons disease Science Translational Medicine, 8 (342), 342-342 DOI: 10.1126/scitranslmed.aaf3634

Hollis, F., van der Kooij, M., Zanoletti, O., Lozano, L., Cantó, C., & Sandi, C. (2015). Mitochondrial function in the brain links anxiety with social subordination Proceedings of the National Academy of Sciences, 112 (50), 15486-15491 DOI: 10.1073/pnas.1512653112

Machado, A., Pan, A., da Silva, T., Duong, A., & Andreazza, A. (2016). Upstream Pathways Controlling Mitochondrial Function in Major Psychosis: A Focus on Bipolar Disorder The Canadian Journal of Psychiatry, 61 (8), 446-456 DOI: 10.1177/0706743716648297

Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, Jia P, Assadzadeh A, Flanagan J, Schumacher A, Wang SC, & Petronis A (2008). Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. American journal of human genetics, 82 (3), 696-711 PMID: 18319075

Radak Z, Chung HY, & Goto S (2008). Systemic adaptation to oxidative challenge induced by regular exercise. Free radical biology & medicine, 44 (2), 153-9 PMID: 18191751

Scaini, G., Rezin, G., Carvalho, A., Streck, E., Berk, M., & Quevedo, J. (2016). Mitochondrial dysfunction in bipolar disorder: Evidence, pathophysiology and translational implications Neuroscience & Biobehavioral Reviews, 68, 694-713 DOI: 10.1016/j.neubiorev.2016.06.040

van der Wijst, M., & Rots, M. (2015). Mitochondrial epigenetics: an overlooked layer of regulation? Trends in Genetics, 31 (7), 353-356 DOI: 10.1016/j.tig.2015.03.009

Wang C, Du W, Su QP, Zhu M, Feng P, Li Y, Zhou Y, Mi N, Zhu Y, Jiang D, Zhang S, Zhang Z, Sun Y, & Yu L (2015). Dynamic tubulation of mitochondria drives mitochondrial network formation. Cell research, 25 (10), 1108-20 PMID: 26206315

Image via DasWortgewand / Pixabay.

Carla Clark, PhD

Carla Clark, PhD, is BrainBlogger's Psychology and Psychiatry Section Editor and a scientific consultant, writer and researcher in fields including psychology and neuropsychology, as well as biotechnology, molecular biology and biophysical chemistry. She is also our newly appointed Digital and Social Media Manager. Follow her on Facebook or Twitter @GeekReports
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