Severe life stress, mitochondrial dysfunction, and depressive behavior: A pathophysiological and therapeutic perspective

Mitochondrion. 2021 Jan;56:111-117. doi: 10.1016/j.mito.2020.11.010. Epub 2020 Nov 19.


Mitochondria are responsible for providing our cells with energy, as well as regulating oxidative stress and apoptosis, and considerable evidence demonstrates that mitochondria-related alterations are prevalent during chronic stress and depression. Here, we discuss how chronic stress may induce depressive behavior by potentiating mitochondrial allostatic load, which ultimately decreases energy production, elevates the generation of harmful reactive oxygen species, damages mitochondrial DNA and increases membrane permeability and pro-apoptotic factor release. We also discuss how mitochondrial insults can exacerbate the immune response, contributing to depressive symptomology. Furthermore, we illustrate how depression symptoms are associated with specific mitochondrial defects, and how targeting of these defects with pharmacological agents may be a promising avenue for the development of novel, more efficacious antidepressants. In summary, this review supports the notion that severe psychosocial stress induces mitochondrial dysfunction, thereby increasing the vulnerability to developing depressive symptoms.

Keywords: Antidepressants; Depression; Mitochondria; Oxidative stress; Reelin; Stress.

Publication types

  • Review

MeSH terms

  • Apoptosis
  • DNA, Mitochondrial / genetics*
  • Depression / genetics*
  • Depression / metabolism
  • Energy Metabolism
  • Gene Expression Regulation
  • Humans
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Oxidative Stress
  • Stress, Psychological / genetics*
  • Stress, Psychological / metabolism


  • DNA, Mitochondrial