Mitochondria and the economy of stress (mal)adaptation

Stress-associated diseases, like depression have a life time prevalence of up to 20%, and approximately 18.4 million people in Europe suffer from depression. Despite decades of research, we still do not understand completely this complex brain disease. Increasing body of correlative evidence implicates mitochondria in the aetiology of depression, but the fundamental question of how suboptimal mitochondrial function causes depression remains to be answered. Here we propose that the balance between cost of adaptation to our ever changing environment (stress) and available energy (mitochondrial function) is crucial for mental health. More specifically, stress activates the brain, and changes its structure and function (neuronal plasticity). This comes at a metabolic cost that is primarily met by energy produced by mitochondria. Individuals with optimal mitochondrial function could meet critical energy demands of stress-induced neuronal-plasticity, thus are at relatively low risk for depression. In contrast, in individuals with suboptimal mitochondrial function stress-associated depletion of the brain's energy resources could ultimately compromise neuronal plasticity that in-time could render an individual vulnerable for depression. Naturally, this does not imply that all mitochondrial patients suffer from depression, or that all depressed patients have underlying mitochondrial pathology. It, however, does imply that suboptimal mitochondrial function could be pathogenic in a subgroup of patients with depression. If so, this will not only have a profound effect on our understanding of depression, but on therapy and counselling, that will also be discussed.

► Suboptimal mitochondrial function is documented in individuals with depression.
► Markedly increased frequency of depression in patients with mitochondrial disorders.
► Mitochondrial efficiency underlies vulnerability to depression.
► Suboptimal mitochondrial function is pathogenic in a subgroup of patients with depression.