Ruth F. McCan, David A. Ross
Many neuronal functions need mitochondria. Therefore, one would expect mitochondrial damage to to affect the nervous system. Indeed, we see a higher than normal incidence of psychiatric illnesses in people with genetic mitochondrial disorders and depressive episodes have been observed in mouse model of genetic mitochondrial diseases.
Another area of research is exploring the other direction of causality: can psychological stress and depression cause mitochondrial dysfunctions?
One proposed mechanism involves glucocorticoids. Experiments with cultured mouse neurons suggest that mitochondria are impaired by long-term exposure to glucocorticoids, which may be overproduced in states of stress and depression.
Another hypothesis involves oxidative stress (OS), caused by reactive oxygen species (ROS), which are produced by mitochondria. Biomarkers of OS are increased in people with depression, and other mood and anxiety disorders seem associated to OS. It might be that stress leads to a hyper-metabolic state in which mitochondria produce more ROS. These are toxic to mitochondria themselves, which are very vulnerable to oxidative damage, potentially causing more ROS production in a vicious cycle.
A study highlighting potential connections between stress, depression and mitochondria was published in 2015 by Cai et al., who collaborated with more than 60 scientists to look at a cohort of 11,670 women from China, through whole-genome sequencing of saliva samples.
It was found that women who had experienced stressful life events and depression had shortened telomeres, something which can be seen in settings of OS. It might be that stress acts on mitochondria, triggering a cascade which leads to depression. However, another possible explanation can be that stress take people who are more prone to depression and triggers an overdrive state in which mitochondria become overwhelmed, leading to OS. Therefore, it is not clear whether mitochondrial dysfunctions cause stress or the other way around.
Another question which is attracting interest concerns our mitochondria are involved in synaptic health and dysfunction in depression. It is thought that in depression neurons atrophy, synapses vanish and dendrites shrink. Although it is not clear whether or not (and how) these morphological changes are causally connected to the disease, it is worth considering the underlying mechanism. It is easy to imagine that large amounts of energy are required to create new neurons and synapses, so it is likely that mitochondria play a role. Moreover, mitochondria are involved in the regulation of intracellular calcium leves, which is crucial at synapses, since calcium stimulates neurotransmitter release.
It is clear that the more we learn about mitochondria, the more they can help unravel the connections between neurotransmitters, mood states, genetic diseases and psychiatric symptoms, life experiences and mental health.