The many faces of mitochondrial dysfunction in depression: From pathology to treatment

Introduction The last years of neurobiological research have transformed the way we consider mental illnesses. We have gone from a deterministic genetic view to a broader vision that includes the involvement of non-cerebral systems. This is especially true for major depression (MD). Historically, MD has been perceived as a multifactorial disorder correlated to various neurobiological changes like neurotransmitter deficits, endocrine disturbances, impaired plasticity, and neural adaptation (Benatti et al., 2016). Indeed, the development and progression of depressive disorders has been conceived as the disruption of body allostasis, defined as the process of achieving stability of physiological and mental processes through dynamic change (Wang et al., 2019). The main player in the “allostatic game” is the brain, an organ designed to integrate signals from the periphery that anticipate fluctuations, changes, and needs and coordinates allostatic mediators in order to develop successful coping mechanisms that ultimately lead to an adaptative strategy and resilience (de Kloet et al., 2005). The establishment and maintenance of these mechanisms requires large amounts of energy from the organism. Without energy, or in a partial lack of energy, the biological mechanisms necessary to respond appropriately to stimuli may not occur or be established incorrectly or abnormally. Human and animal studies suggest an intriguing link between our body’s ability to produce energy and the brain’s ability to correctly perform the complex cellular and molecular processes involved in allostatic processes. In eukaryotic cells, mitochondria are the powerhouse that produces and distributes energy to all other components. Functional or quantitative alterations of the ability of mitochondria to adequately supply energy can have important repercussions primarily on cellular processes and cascades of serial events (Herst et al., 2017) as well as on the correct functioning of the organism including mechanisms of brain plasticity, mood, and behavior in general (Allen et al., 2018). In this framework, it is particularly intriguing to think of the mitochondria as an active regulator of many of the biological phenomena involved in depression and in the efficacy of or resistance to the most widely used pharmacological treatments. Once the energetic equilibrium is compromised, the body becomes more “vulnerable.” This is especially true for stress-related disorders, such as depression. In fact, depression is often associated with energetic imbalance leading to profound effects on the disease (Zuccoli et al., 2017). The driving questions then are as follows: What happens to the brain in the presence of an energetic imbalance? Does depression or depression-related symptoms impact mitochondrial energetic efficiency? Is antidepressant efficacy mediated by mitochondrial functionality