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Review
. 2021 Nov:61:1-10.
doi: 10.1016/j.mito.2021.08.016. Epub 2021 Aug 31.

Mitophagy in depression: Pathophysiology and treatment targets

Ashutosh Tripathi  1 , Giselli Scaini  2 , Tatiana Barichello  3 , João Quevedo  4 , Anilkumar Pillai  5
Affiliations
Review

Mitophagy in depression: Pathophysiology and treatment targets

Ashutosh Tripathi et al. Mitochondrion. 2021 Nov.

Abstract

Mitochondria, the 'powerhouse' of eukaryotic cells, play a key role in cellular homeostasis. However, defective mitochondria increase mitochondrial ROS (mtROS) production and cell-free mitochondrial DNA (mtDNA) release, leading to increased inflammation. Mitophagy is a vital pathway, which selectively removes defective mitochondria through the process of autophagy. Thus, an impairment in the mitophagy pathway might trigger the gradual accumulation of defective mitochondria. Accumulating evidence suggest that inflammation and mitochondrial dysfunction are linked to the pathogenesis of depression. In this article, we have reviewed the role of impaired mitophagy as a contributing factor in depression pathophysiology. Further, we have discussed the potential therapeutic interventions aimed at modulating mitophagy in depression.

Keywords: Depression; Mitochondria; Mitophagy; Therapeutics.

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Figures

Figure 1.
Figure 1.. The role of mitophagy in immune dysfunction and behavior deficits in depression.
The removal of defective mitochondria involves Ub-dependent PINK1/Parkin pathway and Ub-independent receptor-mediated pathway, which lead to the engulfment of defective mitochondria by autophagosome, called as mitophagosome. Mitophagosome fuses with the lysosomes, where lysosomal enzymes degrade the mitochondria. Under chronic stress conditions, mitophagy machinery becomes dysfunctional and leads to the accumulation of defective mitochondria, and increased levels of mtROS and cf-mtDNA. These changes result in increased pro-inflammatory cytokines, immune dysfunction and behavior deficits. Rapamycin induces autophagy by inhibiting mTOR and also by increasing the expression of p62 and PINK1/Parkin. Both rapamycin and mitoTEMPO inhibit mtROS. Metformin increases PINK1/Parkin pathway and mitophagosome formation. Resveratrol is known to increase both PINK1/Parkin and BNIP3 mediated mitophagy. The non-pharmacological approaches like intermittent fasting and caloric restriction increase PINK1/Parkin and BNIP3 mediated mitophagy. Ub-Ubiquitin; BNIP3- BCL2 and adenovirus E1B 19-kDa-interacting protein 3; BNIP3L/NIX-(BCL2 interacting protein 3 like); PINK1-PTEN-induced putative kinase 1; cf-mtDNA-cell-free mtDNA; mtROS-mitochondrial ROS
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