Resilience to Depression: the Role of Mitochondrial Dynamics Regulatory Proteins

Affecting around 350 million people worldwide, depression is the most prevalent and complex psychiatric disorder and remains a devastating illness. The World Health Organization projects that by 2020 it will be the highest contributor to the global burden of disease. Yet our understanding of its mechanisms is still limited. Moreover, the existence of high rates (around 40%) of non-responsive patients to current pharmacotherapies necessitates development of novel and more effective strategies to treat depression. Increasing evidence suggests that depression is highly associated with impaired mitochondrial function (NB: mitochondria’s most prominent roles are to produce energy of the cell) in the brain such as decreased respiration, bioenergetics defects, imbalanced antioxidant defense mechanism, and altered mitochondrial dynamics. Human observations report that more than 50% of patients with mitochondrial diseases exhibit clinical symptoms of depression, and depressive symptoms often precede the other symptoms of the underlying mitochondrial disease. However, the underlying cellular and molecular mechanisms remain unresolved.

Recent studies have demonstrated a link between depression susceptibility and mitochondrial dysfunction in the nucleus accumbens (NAc), a crucial mood-and reward-regulatory brain region. Dr. Sriparna Ghosal, an AXA Research Fund grantee at École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland, has recently gained significant insight into the mechanisms underpinning this connection, and opened up the perspective to target mitofusin 1 (MFN1), a key mitochondrial fusion protein involved in maintaining mitochondrial dynamics and health, to ameliorate depression-related deficits. Her project, she explains: “aims to unravel how mitofusin 1 deficiency increases susceptibility to depression, from cellular level, to neuronal activity and brain circuitry and ultimately behavior”.

The overall objective of this undertaking is to identify novel molecular underpinnings of depression that will allow for the development of more effective therapeutic interventions. “A successful outcome of the research, Dr. Ghosal points out, will establish a major conceptual advancement in understanding the neural and mitochondrial basis of depression and several other mitochondrial dysfunction-induced affective disorders”.