Changes of TSPO-mediated mitophagy signaling pathway in learned helplessness mice

Highlights

• TSPO expression significantly decreased in the brain of LH mice.

• Several TSPO downstream mitophagy signal molecules were also down-regulated.

• TSPO may be potential therapeutic target for depression treatment.

Abstract

Low response rate was witnessed with the present monoaminergic based antidepressants, urging a need for new therapeutic target identification. Accumulated evidences strongly suggest that mitochondrial deficit is implicated in major depression and 18 kDa translocator protein (TSPO) plays an important role in regulating mitochondrial function. However the changes of TSPO and TSPO mediated mitophagy pathway in the depressive brain is unclear. In present study, a well validated animal model of depression, learned helplessness (LH), was employed to investigate the relevant changes. Significant behavioral changes were observed in the LH mice. Results showed that TSPO and other mitophagy related proteins, such as VDAC1, Pink1 and Beclin1 were significantly decreased by LH challenge. Moreover, KIFC2, relevant to the mitochondrial transport and Snap25, relevant to neurotransmitter vesicle release, were also obviously down-regulated in the LH mice, which further rendered supportive evidence for the existing mitochondrial dysfunction in LH mice. Present results demonstrated that LH induced depressive symptoms and affected TSPO-mediated mitophagy pathway, indicating a potential target candidate for depression treatment.

Introduction

Depression is a common emotional and mental disorder, with essential features of continuous pernicious mental stimulation, depressed mood, loss of interest, self-accusation and self-guilty, suicidality and thought slowness, which is often accompany with cognitive or psychomotor disorders or several changes of physiological functions. The lifetime prevalence of major depressive disorder is 17% of the population and brings about tremendous secondary costs to society (Kessler et al., 2005, Wang et al., 2003). Most current pharmacologic antidepressant treatments target either or both serotonin and norepinephrine systems in the brain to alleviate depressive symptoms (Kennedy and Rizvi, 2009). However, more than 30% of patients with major depressive disorder fail to respond to these antidepressants, reflecting our incomplete understanding to the etiology of depression and inciting a need for alternative treatment strategies.

A growing body of evidence shows that mitochondrial dysfunction and its consequences play a pivotal role in the pathogenesis of depression (Klinedinst and Regenold, 2014). Mitochondria are well known to be vital organelles with multiple functions for neuronal survival and activity. Mitochondrial dysfunction can lead to a decline in energy production, generation of reactive oxygen species and consequently mitochondrial-induced apoptosis. Mitophagy, a conserved lysosomal degradation pathway, is essential for mitochondrial quality control in the central nervous system. Many studies have shown that antidepressants regulate autophagy and some antidepressants were found to be involved in the neuronal autophagy signaling pathway (Gassen et al., 2015). Amitriptyline and citalopram have been reported to increase the expression of the autophagic markers LC3-II and Beclin1 (Zschocke et al., 2011). These findings suggest that neuronal autophagy signaling pathways play an important role in major depressive disorder.

Recently, the role of the 18 kDa translocator protein (TSPO), an important rate limiting step in neurosteroidogenesis, has received increased attention in the pathophysiology of the stress response and stress-related disorders (Beurdeley-Thomas et al., 2000, Pinna et al., 2006, Pinna and Rasmusson, 2012). TSPO inhibits mitochondrial autophagy downstream of the PINK1/Parkin pathway, preventing essential ubiquitination of proteins (Gatliff et al., 2014), but this study concentrates on the cell research and not mentions any disease model. The modulation of mitophagy by TSPO is dependent on VDAC1, a voltage-dependent anion channel, to which TSPO binds. VDAC1 is necessary for PINK1/Parkin-directed autophagy of damaged mitochondria (Geisler et al., 2010), which specifically interact with Parkin on defective mitochondria and are required for efficient targeting of Parkin to mitochondria and subsequent mitophagy (Sun et al., 2012). TSPO density has been found to be altered in anxiety disorders (Droogleever Fortuyn et al., 2004, Papadopoulos et al., 2006). Decreased platelet TSPO levels have been found in the adolescent inpatients with repeated suicide attempts (Soreni et al., 1999), but the expression of TSPO in the brain was inconsistently reported (Hannestad et al., 2013, Setiawan et al., 2015).

As mentioned above, changes in TSPO expression and related signaling components in distinct brain areas of depressive patient remains to be investigated. The present study employed learned helplessness depression model (LH), which is a common stress-related animal model of depression-like behavior, to investigate the changes of TSPO-related pathway.