Major depressive disorder (MDD) is a globally occurring phenomenon and developed into a severe socio-economic challenge. Despite decades of research, the underlying pathophysiological processes of MDD remain incompletely resolved. Like other mental disorders, MDD is hypothesized to mainly affect the central nervous system (CNS). An increasing body of research indicates MDD to also change somatic functioning, which impairs the physiological performance of the whole organism. As a consequence, a paradigm shift seems reasonable towards a systemic view of how MDD affects the body. The same applies to treatment strategies, which mainly focus on the CNS. One new approach highlights changes in the bioenergetic supply and intracellular network dynamics of mitochondria for the pathophysiological understanding of MDD. Mitochondria, organelles of mostly all eukaryotic cells, use carbon compounds to provide biochemical energy in terms of adenosine triphosphate (ATP). ATP is the bioenergetic currency and the main driver for enzymatic activity in all cells and tissues. Clinical symptoms of MDD including fatigue, difficulties concentrating, and lack of motivation were reported to be associated with impaired mitochondrial ATP production and changes in the density of the mitochondrial network. Additionally, the severity of these symptoms correlates negatively with mitochondrial functioning. Psychotherapy, antidepressant medication, and electroconvulsive therapy (ECT), a method used to treat severe and treatment-resistant forms of MDD, achieve robust antidepressant effects. The biological mechanisms beyond the treatment response to antidepressant strategies are partially understood. Here, mitochondrial functioning is discussed as a promising new biomarker for diagnosis and treatment effects in MDD.